Oxymetazoline compositions

ABSTRACT

The present disclosure is directed to compositions comprising oxymetazoline and methods of stabilizing oxymetazoline compositions for long term storage.

FIELD OF THE INVENTION

This invention relates to compositions comprising oxymetazoline,pharmaceutically acceptable salts of oxymetazoline, and methods forpreparing and using them.

BACKGROUND OF THE INVENTION

Blepharoptosis (commonly known as ptosis) is abnormal partial orcomplete drooping of the upper eyelid that usually occurs from a partialor complete dysfunction of the muscles that elevate the upper eyelid:the levator palpebrae superioris and/or the Müller's muscle. Ptosisoccurs when the muscles that raise the eyelid (levator palpebraesuperioris and/or Müller's muscles) are not strong enough to do soproperly. It can affect one eye or both eyes and is more common in theelderly, as muscles in the eyelids begin to deteriorate. It is one ofthe most common eyelid disorders, occurring in approximately 12% ofadults over the age of 50 (G. V. Sridharan, R. C. Tallis, B.Leatherbarrow, W. M. Forman, A., Community Survey of Ptosis of theEyelid and Pupil Size of Elderly People, Age and Ageing, Volume 24,Issue 1, January 1995, pp. 21-24). Ptosis is classified as eithercongenital or acquired. Acquired ptosis has numerous etiologies but mostoften is aponeurotic, a result of involutional changes to the levatoraponeurosis or a result of stretching or disruption during cataractsurgery, lens replacement, or as a result of long-term contact lenswear, both hard and soft lenses. (Custer P. L., (2008) Blepharoptosis.In: Yanoff M., Duker J. S., editors. Ophthalmology. 3rd ed. St. Louis,Mo.: Mosby Elsevier; p. 1397-1403; van den Bosch W A, Lemij H. G.,Blepharoptosis induced by prolonged hard contact lens wear.Ophthalmology. 1992; 99:1759-65; Kersten R. C., Conciliis C., Kulwin D.R., Acquired ptosis in the young and middle-aged adult population.Ophthalmology. 1995; 102:924-8; Reddy A. K., Foroozan R., Arat Y. O.,Edmond J. C., Yen M. T., Ptosis in young soft contact lens wearers.Ophthalmology. 2007; 114:2370.)

Patients with ptosis may experience significant superior visual fielddefects, which can affect daily activities such as driving, crossingstreets, and reading. Treatment for acquired ptosis usually involvessurgery, with risks of infection, bleeding, over- or under-correction,reduced vision, and lagophthalmos (inability to close the eyelidscompletely) (Finsterer J., Ptosis: causes, presentation, and management.Aesthetic Plast. Surg. 2003; 27(3):193-204). Mechanical treatment ofptosis (scleral contact lenses with a bar to lift the eyelid, eyelidptosis crutches attached to glasses, or adhesive tape or putty to affixthe upper eyelid to the supraorbital structures) is limited by patientdissatisfaction with physical appearance, contact allergies, or skinirritation. (Shah-Desai S. D., Aslam S. A., Pullum K., Beaconsfield M.,Rose G. E., Scleral contact lens usage in patients with complexblepharoptosis. Ophthal. Plast. Reconstr. Surg. 2011 March-April;27(2):95-8.) Pharmacologic treatment of ptosis has not been pursuedbecause the agents that have been evaluated (e.g., epinephrine,dipivefrin, apraclonidine, phenylephrine, brimonidine) either causedmydriasis, resulting in blurred vision or photophobia, or unacceptablesystemic side effects. (Matjucha I. C., The nonsurgical treatment ofptosis. In: Cohen A. J., Weinberg D. A., editors: Evaluation andmanagement of blepharoptosis. New York: Springer, 2011. pp. 155-61;Scheinfeld N., The use of apraclonidine eyedrops to treat ptosis afterthe administration of botulinum toxin to the upper face. Dermatol.Online J. 2005 Mar. 1; 11(1):9; Kass M. A., Mandell A. I., Goldberg I.,Paine J. M., Becker B., Dipivefrin and epinephrine treatment of elevatedintraocular pressure: a comparative study. Arch. Ophthalmol. 1979October; 97(10):1865-6; Fraunfelder F. T., Scafidi A. F., Possibleadverse effects from topical ocular 10% phenylephrine. Am. J.Ophthalmol. 1978; 85(4):447-53.)

Oxymetazoline hydrochloride,6-tert-Butyl-3-(2-imidazolin-2-ylmethyl)-2,4-dimethylphenolmonohydrochloride or Phenol,3-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-6-(1,1-dimethylethyl)-2,4-dimethyl-,monohydrochloride, is an α-adrenergic agonist. Oxymetazoline is a directacting sympathomimetic amine, which acts on alpha-adrenergic receptorsin the arterioles of the conjunctiva and nasal mucosa.

To address the ongoing challenge of balancing the efficacies with therelative risk of adverse events, a novel ophthalmic formulation ofoxymetazoline hydrochloride was developed.

BRIEF SUMMARY OF THE INVENTION

In some aspects, the compositions of the present disclosure are relatedto an aqueous pharmaceutically stable ophthalmic formulation comprising:about 0.1 wt % oxymetazoline hydrochloride; from about 0.2 wt % to about1.0 wt % sodium chloride; from about 0.05 wt % to about 0.10 wt %potassium chloride; from about 0.02 wt % to about 0.06 wt % calciumchloride; from about 0.01 wt % to about 0.05 wt % magnesium chloride;one or more suitable buffers; from about 0.1 wt % to about 0.90 wt %hypromellose; and optionally a pH adjuster; wherein the formulation hasa pH range from about 6.3 to about 6.5. In some aspects, the one or moresuitable buffers comprise from about 0.05 wt % to about 1.0 wt %. Insome aspects, the one or more suitable buffers comprise sodium acetatetrihydrate and sodium citrate. In some aspects, the one or more suitablebuffers comprise about 0.39 wt % sodium acetate trihydrate and about0.17 wt % sodium citrate. In some aspects, the formulation comprisesabout 0.64 wt % sodium chloride, about 0.075 wt % potassium chloride,about 0.048 wt % calcium chloride dihydrate, and about 0.03 wt %magnesium chloride hexahydrate. In some aspects, the pH adjuster isselected from the group consisting of acetic acid, hydrochloric acid,sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calciumcarbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide,ammonium hydroxide, ammonium phosphate, and a combination thereof. Insome aspects, the pH adjuster comprises hydrochloric acid. In someaspects, the formulation does not comprise a preservative. In someaspects, the formulation is stable for a period of 0-24 months. In someaspects, the formulation is stable for a period of at least 24 months.In some aspects, the formulation is stable at 25° C. and 40% relativehumidity for a period of at least 24 months. In some aspects, thecomposition is formulated in a single use container. In some aspects,the volume of the single use container is about 0.5 mL. In some aspects,the single use container is in child resistant packaging. In someaspects, the single use container delivers about 0.035 mg ofoxymetazoline hydrochloride per drop.

The compositions of the present disclosure are also related to anaqueous pharmaceutically stable ophthalmic formulation consisting of:about 0.1 wt % oxymetazoline hydrochloride; from about 0.2 wt % to about1.0 wt % sodium chloride; from about 0.05 wt % to about 0.10 wt %potassium chloride; from about 0.02 wt % to about 0.06 wt % calciumchloride; from about 0.01 wt % to about 0.05 wt % magnesium chloride;one or more suitable buffers; from about 0.1 wt % to about 0.90 wt %hypromellose; and optionally a pH adjuster; wherein the formulation hasa pH range from about 6.3 to about 6.5. In some aspects, the one or moresuitable buffers comprise from about 0.05 wt % to about 1.0 wt %. Insome aspects, the one or more suitable buffers comprise sodium acetatetrihydrate and sodium citrate. In some aspects, the one or more suitablebuffers comprise about 0.39 wt % sodium acetate trihydrate and about0.17 wt % sodium citrate. In some aspects, the formulation comprisesabout 0.64 wt % sodium chloride, about 0.075 wt % potassium chloride,about 0.048 wt % calcium chloride dihydrate, and about 0.03 wt %magnesium chloride hexahydrate. In some aspects, the pH adjuster isselected from the group consisting of acetic acid, hydrochloric acid,sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calciumcarbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide,ammonium hydroxide, ammonium phosphate, and a combination thereof. Insome aspects, the pH adjuster comprises hydrochloric acid. In someaspects, the formulation is stable for a period of 0-24 months. In someaspects, the formulation is stable for a period of at least 24 months.In some aspects, the formulation is stable at 25° C. and 40% relativehumidity for a period of at least 24 months. In some aspects, thecomposition is formulated in a single use container. In some aspects,the volume of the single use container is about 0.5 mL. In some aspects,the single use container is in child resistant packaging. In someaspects, the single use container is in a child resistant pouch. In someaspects, the single use container delivers about 0.035 mg ofoxymetazoline hydrochloride per drop.

The compositions of the present disclosure are also related to anaqueous pharmaceutically stable ophthalmic preservative-free formulationcomprising: about 0.1 wt % oxymetazoline hydrochloride; about 0.64 wt %sodium chloride; about 0.075 wt % potassium chloride; about 0.048 wt %calcium chloride dihydrate; about 0.03 wt % magnesium chloridehexahydrate; one or more suitable buffers; about 0.5 wt % hypromellose;and optionally hydrochloric acid; wherein the formulation has a pH rangefrom about 6.3 to about 6.5.

The methods of the present disclosure are related to a method oftreating ptosis in a subject, comprising administering to at least oneeye of the subject a therapeutically effective amount of an aqueouspharmaceutically stable ophthalmic preservative-free formulationcomprising: about 0.1 wt % oxymetazoline hydrochloride; from about 0.2wt % to about 1.0 wt % sodium chloride; from about 0.05 wt % to about0.10 wt % potassium chloride; from about 0.02 wt % to about 0.06 wt %calcium chloride; from about 0.01 wt % to about 0.05 wt % magnesiumchloride; one or more suitable buffers; from about 0.1 wt % to about0.90 wt % hypromellose; and optionally hydrochloric acid; wherein theaqueous pharmaceutically stable ophthalmic formulation has a pH rangefrom about 6.3 to about 6.5. In some aspects, the ptosis is acquiredblepharoptosis. In some aspects, the formulation is administered to thesubject on one or more consecutive days at a dose of one drop in eacheye for a total daily dose of about 0.07 mg oxymetazoline hydrochloride.

In some aspects, a mean C_(max) after a single-dose administration ofthe formulation is from about 25 to about 35 pg/ml. In some aspects, amean AUC_(0-∞) after a single-dose administration of the formulation isfrom about 300 to about 700 pg·h/mL. In some aspects, a T_(max) after asingle-dose administration of the formulation is from about 0.5 to about6 hours. In some aspects, the methods of the present disclosure arerelated to a method of treating ptosis using an aqueous pharmaceuticallystable ophthalmic preservative-free formulation comprising: about 0.64wt % sodium chloride; about 0.075 wt % potassium chloride; about 0.048wt % calcium chloride dihydrate; about 0.03 wt % magnesium chloridehexahydrate; and about 0.5 wt % hypromellose.

The methods of the present disclosure are also related to a method ofincreasing the vertical separation of the upper and lower eyelids in asubject, comprising administering to at least one eye of the subject anaqueous pharmaceutically stable ophthalmic preservative-free formulationcomprising: about 0.1 wt % oxymetazoline hydrochloride; from about 0.2wt % to about 1.0 wt % sodium chloride; from about 0.05 wt % to about0.10 wt % potassium chloride; from about 0.02 wt % to about 0.06 wt %calcium chloride; from about 0.01 wt % to about 0.05 wt % magnesiumchloride; one or more suitable buffers; from about 0.1 wt % to about0.90 wt % hypromellose; and optionally hydrochloric acid; wherein theaqueous pharmaceutically stable ophthalmic formulation has a pH rangefrom about 6.3 to about 6.5.

In some aspects, the formulation is administered to the subject on oneor more consecutive days at a dose of one drop in a single eye for atotal daily dose of about 0.035 mg oxymetazoline hydrochloride. In someaspects, the formulation is administered to the subject on one or moreconsecutive days at a dose of one drop in each eye for a total dailydose of about 0.07 mg oxymetazoline hydrochloride. In some aspects, amean C_(max) after a single-dose administration of the formulation isfrom about 25 to about 35 pg/ml. In some aspects, a mean AUC_(0-∞) aftera single-dose administration of the formulation is from about 300 toabout 700 pg·h/mL. In some aspects, a T_(max) after a single-doseadministration of the formulation is from about 0.5 to about 6 hours.

In some aspects, the aqueous pharmaceutically stable ophthalmicpreservative-free formulation comprises: about 0.64 wt % sodiumchloride; about 0.075 wt % potassium chloride; about 0.048 wt % calciumchloride dihydrate; about 0.03 wt % magnesium chloride hexahydrate; andabout 0.5 wt % hypromellose.

The methods of the present disclosure are also directed to a method ofimproving a Leicester Peripheral Field Test (LPFT) score in a subject,comprising administering to at least one eye of the subject an aqueouspharmaceutically stable ophthalmic preservative-free formulationcomprising: about 0.1 wt % oxymetazoline hydrochloride; from about 0.2wt % to about 1.0 wt % sodium chloride; from about 0.05 wt % to about0.10 wt % potassium chloride; from about 0.02 wt % to about 0.06 wt %calcium chloride; from about 0.01 wt % to about 0.05 wt % magnesiumchloride; one or more suitable buffers; from about 0.1 wt % to about0.90 wt % hypromellose; and optionally hydrochloric acid; wherein theaqueous pharmaceutically stable ophthalmic formulation has a pH rangefrom about 6.3 to about 6.5, and whereby the mean LPFT score isincreased by about 5-10 points after about 0.1-16 hours afteradministration. In some aspects, the formulation is administered to thesubject on one or more consecutive days at a dose of one drop in eacheye for a total daily dose of about 0.07 mg oxymetazoline hydrochloride.In some aspects, a mean Cmax after a single-dose administration of theformulation is from about 25 to about 35 pg/ml. In some aspects, a meanAUC_(0-∞) after a single-dose administration of the formulation is fromabout 300 to about 700 pg·h/mL. In some aspects, a T_(max) after asingle-dose administration of the formulation is from about 0.5 to about6 hours. In some aspects, the Leicester Peripheral Field Test (LPFT)median score is increased by about 5-10 points after about 6 hours afteradministration. In some aspects, tachyphylaxis is not exhibited for atleast six weeks. In some aspects, the aqueous pharmaceutically stableophthalmic preservative-free formulation comprises: about 0.64 wt %sodium chloride; about 0.075 wt % potassium chloride; about 0.048 wt %calcium chloride dihydrate; about 0.03 wt % magnesium chloridehexahydrate; and about 0.5 wt % hypromellose.

The methods of the present disclosure are also related to a method ofimproving a Marginal Reflex Distance Test 1 (MRD-1) score in a subject,comprising administering to at least one eye of the subject an aqueouspharmaceutically stable ophthalmic preservative-free formulationcomprising: about 0.1 wt % oxymetazoline hydrochloride; from about 0.2wt % to about 1.0 wt % sodium chloride; from about 0.05 wt % to about0.10 wt % potassium chloride; from about 0.02 wt % to about 0.06 wt %calcium chloride; from about 0.01 wt % to about 0.05 wt % magnesiumchloride; one or more suitable buffers; from about 0.1 wt % to about0.90 wt % hypromellose; and optionally hydrochloric acid; wherein theaqueous pharmaceutically stable ophthalmic formulation has a pH rangefrom about 6.3 to about 6.5, and whereby the mean score is increased byabout 0.2-1.5 points after about 1-20 minutes after administration orafter about 1-6 hours, e.g., 8 hours, after administration. In someaspects, the aqueous pharmaceutically stable ophthalmic formulation isadministered to the subject on one or more consecutive days at a dose ofone drop in each eye for a total daily dose of about 0.07 mgoxymetazoline hydrochloride. In some aspects, a mean C_(max) after asingle-dose administration of the formulation is from about 25 to about35 pg/ml. In some aspects, a mean AUC_(0-∞) after a single-doseadministration of the formulation is from about 300 to about 700pg·h/mL. In some aspects, a T_(max) after a single-dose administrationof the formulation is from about 0.5 to about 6 hours. In some aspects,the Marginal Reflex Distance Test 1 (MRD-1) mean score is increased byabout 0.2-1.0 points after about 5 minutes after administration. In someaspects, tachyphylaxis is not exhibited for at least six weeks. In someaspects, the aqueous pharmaceutically stable ophthalmicpreservative-free formulation comprises: about 0.64 wt % sodiumchloride; about 0.075 wt % potassium chloride; about 0.048 wt % calciumchloride dihydrate; about 0.03 wt % magnesium chloride hexahydrate; andabout 0.5 wt % hypromellose. In some aspects, the use of the presentcompositions and methods does not exhibit tachyphylaxis. In someaspects, tachyphylaxis is not exhibited for 6 weeks. In some aspects,tachyphylaxis is not exhibited for a period of 6 weeks to 3 months. Insome aspects, tachyphylaxis is not exhibited for a period of 6 weeks, 7weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 1 month, 2 months, or 3months. In some aspects, tachyphylaxis is not exhibited during use ofthe compositions or methods of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean concentration reached after single-dose topicaladministration of 0.1 wt % oxymetazoline HCl ophthalmic solution usingone drop in each eye.

FIG. 2 shows a diagram of the Leicester Peripheral Field Test.

FIGS. 3A and 3B show 24-month and 30-month stability data foroxymetazoline composition batch R60681.

FIGS. 4A and 4B show 24-month and 30-month stability data foroxymetazoline composition batch R60701.

FIGS. 5A and 5B show 24-month and 30-month stability data foroxymetazoline composition batch R60711.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In case of conflict, thepresent application including the definitions will control. Unlessotherwise required by context, singular terms shall include pluralitiesand plural terms shall include the singular. All publications, patentsand other references mentioned herein are incorporated by reference intheir entireties for all purposes as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although methods and materials similar or equivalent to those describedherein can be used in practice or testing of the present disclosure,suitable methods and materials are described below. The materials,methods and examples are illustrative only and are not intended to belimiting. Other features and advantages of the disclosure will beapparent from the detailed description and from the claims.

In order to further define this disclosure, the following terms anddefinitions are provided.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. The terms “a” (or “an”), as wellas the terms “one or more,” and “at least one” can be usedinterchangeably herein. In certain aspects, the term “a” or “an” means“single.” In other aspects, the term “a” or “an” includes “two or more”or “multiple.”

The term “about” is used herein to mean about, roughly, around, or inthe regions of. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10 percent, up or down (higher or lower).

The term “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

The term “pharmaceutically acceptable” as used herein refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically stable” means the ability of thepharmaceutical dosage form to maintain the physical, chemical,therapeutic and microbial properties during the time of storage andusage by the patient.

The term “effective amount” or “pharmaceutically effective amount” asused herein refers to the amount or quantity of a drug orpharmaceutically active substance which is sufficient to elicit therequired or desired therapeutic response, or in other words, the amountwhich is sufficient to elicit an appreciable biological response whenadministered to a patient.

The term “unit dosage form” or “unit dose composition” as used hereinrefers to a device containing a quantity of the therapeutic compound,said quantity being such that one or more predetermined units may beprovided as a single therapeutic administration.

The term “wt %” or “weight/volume” as used herein refers to the ratiobetween to components with respect to volume. For example, a 5 wt %ethanol in water solution would represent a solution comprising 5 gethanol for every 100 mL water.

The term “C_(max)” as used herein refers to the maximum plasmaconcentration of a drug after it is administered to a subject.

The term “T_(max)” as used herein refers to the time required to reachthe maximal plasma concentration (“C_(max)”) after administration of adrug.

The term “AUC” as used herein refers to the area under the curve of aplot of plasma concentration versus time following administration of adrug.

The term “AUC_(0-t)” as used herein refers to the area under the drugconcentration-time curve from time zero to the time of the lastmeasurable concentration (C_(t)).

The term “AUC_(0-∞)” as used herein refers to the area under the drugconcentration-time curve from time zero to infinity. AUC_(0-∞) iscalculated to the last measured concentration (AUC_(0-T)) andextrapolated to infinity (AUC_(t-∞)), for extent of absorption of adrug.

As used herein, the term “free base equivalent” or “FBE” refers to theamount of oxymetazoline present in the oxymetazoline or salt thereof. Inother words, the term “FBE” means either an amount of oxymetazoline freebase, or the equivalent amount of oxymetazoline free base that isprovided by a salt of oxymetazoline. For example, due to the weight ofthe hydrochloride salt, 100 mg of oxymetazoline hydrochloride onlyprovides as much oxymetazoline as 88 mg of the free base form ofoxymetazoline. Other salts are expected to have different conversionfactors, depending on the molecular weight of the salt.

The term “Leicester Peripheral Field Test” or “LPFT” refers to acustomized visual field test designed specifically to assess ptosis (HoS. F., Morawski A., Sampath R., Burns J., Modified visual field test forptosis surgery (Leicester Peripheral Field Test). Eye (Lond). 2011March; 25(3):365-9. doi:10.1038/eye.2010.210. Epub 2011 Jan. 21), and isperformed using a Humphrey Visual Field Analyzer. It is an age-correctedscreening test in which thirty-five points are tested in the superiorfield while 14 points are tested in the inferior field. A maximum of 48°is tested in the superior visual field. The center of fixation isshifted 15° inferiorly to allow for maximum superior field testing. Theinferior field test serves as a reference but is not used in theanalysis.

The term “Marginal Reflex Distance 1 (MRD)” refers to one of two tests.MRD-1 refers to a test that uses photographic measurement of thedistance from the central pupillary light reflex to the central marginof the upper lid. External digital photographs are used to measureMRD-1. Measurements are taken based on the distance from the centralpupillary light reflex to the central margin of the upper lid, ≤2 mm (novisible central pupillary light reflex defaults to 0). MRD-2 refers tothe measurement of the vertical distance from the pupillary center andthe lower eyelid margin.

The term “treating” or “treatment” as used herein refers to theadministration of a composition to a subject for therapeutic purposes.

The term “mean” refers to an average value in a patient population. Forexample, a “mean Cmax” refers to an average of the maximum plasmaconcentration values of a drug in a patient population.

The term “adult” refers to a person 18 years of age or older.

II. Composition

Compositions of the invention include an effective amount of analpha-adrenergic agonist formulated for ophthalmic administration. Theinvention provides compositions and methods useful in the treatment ofptosis. In some aspects, the composition is an ophthalmic solution. Insome aspects, oxymetazoline hydrochloride is formulated for topicalocular delivery as an aseptically prepared, sterile, preservative-freeophthalmic solution (eye drops). The ophthalmic solution can contain 0.1wt % of oxymetazoline hydrochloride in a balanced salt solution with anadded viscosity modifier (hypromellose). It can be filled into clear,unit-dose, 0.5-mL low-density polyethylene (LDPE) blow-fill-seal (BFS)vials, which can be individually packaged in foil pouches.

When administered at 0.1 wt %, oxymetazoline is believed to stimulatethe α2 adrenergic receptors in Müller's muscle causing it to contract,thereby lifting the upper eyelid, and retracting the lower eyelid to alesser degree.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation consisting of: about 0.1 wt % oxymetazolinehydrochloride; from about 0.2 wt % to about 1.0 wt % sodium chloride;from about 0.05 wt % to about 0.10 wt % potassium chloride; from about0.02 wt % to about 0.06 wt % calcium chloride; from about 0.01 wt % toabout 0.05 wt % magnesium chloride; one or more suitable buffers; fromabout 0.1 wt % to about 0.90 wt % hypromellose; and optionally a pHadjuster; wherein the formulation has a pH range from about 6.3 to about6.5.

In some aspects, the one or more suitable buffers comprise from about0.05 wt % to about 1.0 wt %. In some aspects, the one or more suitablebuffers comprise sodium acetate trihydrate and sodium citrate. In someaspects, the formulation comprises about 0.64 wt % sodium chloride,about 0.075 wt % potassium chloride, about 0.048 wt % calcium chloridedihydrate, and about 0.03 wt % magnesium chloride hexahydrate. In someaspects, the pH adjuster is selected from the group consisting of aceticacid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid,calcium acetate, calcium carbonate, ammonium bicarbonate, ammoniumsulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and acombination thereof. In some aspects, the pH adjuster compriseshydrochloric acid.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation comprising: 0.1 wt % oxymetazoline hydrochloride;0.64 wt % sodium chloride; 0.075 wt % potassium chloride; 0.048 wt %calcium chloride dihydrate; 0.03 wt % magnesium chloride hexahydrate;one or more suitable buffers; 0.5 wt % hypromellose; and optionallyhydrochloric acid; wherein the formulation has a pH range from 6.3 to6.5. In some aspects, the one or more suitable buffers comprise sodiumacetate trihydrate, sodium citrate, boric acid, sodium borate, potassiumcitrate, citric acid, sodium bicarbonate,tris(hydroxymethyl)aminomethane (TRIS), and various mixed phosphatebuffers (including combinations of Na₂HPO₄, NaH₂PO₄, and KH₂PO₄) andmixtures thereof. In one aspect, the one or more suitable bufferscomprise 0.39 wt % sodium acetate trihydrate and 0.17 wt % sodiumcitrate.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation consisting essentially of: 0.1 wt % oxymetazolinehydrochloride; 0.64 wt % sodium chloride; 0.075 wt % potassium chloride;0.048 wt % calcium chloride dihydrate; 0.03 wt % magnesium chloridehexahydrate; one or more suitable buffers; 0.5 wt % hypromellose; andoptionally hydrochloric acid; wherein the formulation has a pH rangefrom 6.3 to 6.5. In some aspects, the one or more suitable bufferscomprise sodium acetate trihydrate, sodium citrate, boric acid, sodiumborate, potassium citrate, citric acid, sodium bicarbonate, TRIS, andvarious mixed phosphate buffers (including combinations of Na₂HPO₄,NaH₂PO₄, and KH₂PO₄) and mixtures thereof. In one aspects, the one ormore suitable buffers comprise 0.39 wt % sodium acetate trihydrate and0.17 wt % sodium citrate.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation consisting of: 0.1 wt % oxymetazolinehydrochloride; 0.64 wt % sodium chloride; 0.075 wt % potassium chloride;0.048 wt % calcium chloride dihydrate; 0.03 wt % magnesium chloridehexahydrate; one or more suitable buffers; 0.5 wt % hypromellose; andoptionally hydrochloric acid; wherein the formulation has a pH rangefrom 6.3 to 6.5. In some aspects, the one or more suitable bufferscomprise sodium acetate trihydrate, sodium citrate, boric acid, sodiumborate, potassium citrate, citric acid, sodium bicarbonate, TRIS, andvarious mixed phosphate buffers (including combinations of Na₂HPO₄,NaH₂PO₄, and KH₂PO₄) and mixtures thereof. In one aspect, the one ormore suitable buffers comprise 0.39 wt % sodium acetate trihydrate and0.17 wt % sodium citrate.

One aspect of the invention is a method for treating ptosis in asubject. The method includes the step of administering an effectiveamount of oxymetazoline to an eye of a subject in need of suchtreatment. In some aspects, the method comprises administering to atleast one eye of the subject a therapeutically effective amount of anaqueous pharmaceutically stable ophthalmic formulation comprising: 0.1wt % oxymetazoline hydrochloride; 0.64 wt % sodium chloride; 0.075 wt %potassium chloride; 0.048 wt % calcium chloride dihydrate; 0.03 wt %magnesium chloride hexahydrate; one or more suitable buffers; 0.5 wt %hypromellose; and optionally hydrochloric acid; wherein the formulationhas a pH range from 6.3 to 6.5. In some aspects, the one or moresuitable buffers comprise sodium acetate trihydrate, sodium citrate,boric acid, sodium borate, potassium citrate, citric acid, sodiumbicarbonate, TRIS, and various mixed phosphate buffers (includingcombinations of Na₂HPO₄, NaH₂PO₄, and KH₂PO₄) and mixtures thereof. Inone aspect, the one or more suitable buffers comprise 0.39 wt % sodiumacetate trihydrate and 0.17 wt % sodium citrate.

In some aspects of the invention, the subject is a mammal. In anotheraspect, the mammal is a human.

In some aspects, the formulation is administered at a total daily doseof about 0.07 mg oxymetazoline hydrochloride. In some aspects, theaverage weight of one drop is 0.035 g. In some aspects, one drop isadministered to each eye, and each drop contains approximately 0.035 mgof oxymetazoline hydrochloride (0.0308 mg oxymetazoline free base).

In some aspects, the method comprises administering to at least one eyea therapeutically effective amount of an aqueous pharmaceutically stableophthalmic formulation consisting essentially of: 0.1 wt % oxymetazolinehydrochloride; 0.64 wt % sodium chloride; 0.075 wt % potassium chloride;0.048 wt % calcium chloride dihydrate; 0.03 wt % magnesium chloridehexahydrate; one or more suitable buffers; 0.5 wt % hypromellose; andoptionally hydrochloric acid; wherein the formulation has a pH rangefrom 6.3 to 6.5. In some aspects, the one or more suitable bufferscomprise sodium acetate trihydrate, sodium citrate, boric acid, sodiumborate, potassium citrate, citric acid, sodium bicarbonate, TRIS, andvarious mixed phosphate buffers (including combinations of Na₂HPO₄,NaH₂PO₄, and KH₂PO₄) and mixtures thereof. In some aspects, the one ormore suitable buffers comprise 0.39 wt % sodium acetate trihydrate and0.17 wt % sodium citrate. In some aspects, the formulation isadministered in an amount of about 0.07 mg.

In some aspects, the method comprises administering to at least one eyea therapeutically effective amount of an aqueous pharmaceutically stableophthalmic formulation consisting of: 0.1 wt % oxymetazolinehydrochloride; 0.64 wt % sodium chloride; 0.075 wt % potassium chloride;0.048 wt % calcium chloride dihydrate; 0.03 wt % magnesium chloridehexahydrate; one or more suitable buffers; 0.5 wt % hypromellose; andoptionally hydrochloric acid; wherein the formulation has a pH rangefrom 6.3 to 6.5. In some aspects, the one or more suitable bufferscomprise sodium acetate trihydrate, sodium citrate, boric acid, sodiumborate, potassium citrate, citric acid, sodium bicarbonate, TRIS, andvarious mixed phosphate buffers (including combinations of Na₂HPO₄,NaH₂PO₄, and KH₂PO₄) and mixtures thereof. In some aspects, the one ormore suitable buffers comprise 0.39 wt % sodium acetate trihydrate and0.17 wt % sodium citrate.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation comprising: 0.1 wt % oxymetazoline hydrochloride;0.64 wt % sodium chloride; 0.075 wt % potassium chloride; 0.048 wt %calcium chloride dihydrate; 0.03 wt % magnesium chloride hexahydrate;one or more suitable buffers; 0.5 wt % hypromellose; and optionallyhydrochloric acid; wherein the formulation has a pH range from 6.3 to6.5. In other aspects, the one or more suitable buffers comprise boricacid, sodium borate, potassium citrate, citric acid, sodium bicarbonate,TRIS, and various mixed phosphate buffers (including combinations ofNa₂HPO₄, NaH₂PO₄, and KH₂PO₄) and mixtures thereof. In some aspects, theone or more suitable buffers comprise 0.39 wt % sodium acetatetrihydrate and 0.17 wt % sodium citrate.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation comprising about 0.1 wt %, about 0.2 wt %, about0.3 wt %, about 0.4 wt %, about 0.5 wt %, about 0.6 wt %, about 0.7 wt%, about 0.8 wt %, about 0.9 wt %, or about 1.0 wt % oxymetazolinehydrochloride. In some aspects, the solution is an aqueouspharmaceutically stable ophthalmic formulation comprising about 0.10 wt%, about 0.12 wt %, about 0.13 wt %, about 0.14 wt %, about 0.15 wt %,about 0.16 wt %, about 0.17 wt %, about 0.18 wt %, about 0.19 wt %, orabout 0.20 wt % oxymetazoline hydrochloride. In some aspects, thesolution is an aqueous pharmaceutically stable ophthalmic formulationcomprising about 0.01 wt %, about 0.02 wt %, about 0.03 wt %, about 0.04wt %, about 0.05 wt %, about 0.06 wt %, about 0.07 wt %, about 0.08 wt%, or about 0.09 wt % oxymetazoline hydrochloride.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation consisting essentially of: 0.1 wt % oxymetazolinehydrochloride; 0.64 wt % sodium chloride; 0.075 wt % potassium chloride;0.048 wt % calcium chloride dihydrate; 0.03 wt % magnesium chloridehexahydrate; one or more suitable buffers; 0.5 wt % hypromellose; andoptionally hydrochloric acid; wherein the formulation has a pH rangefrom 6.3 to 6.5. In other aspects, the one or more suitable bufferscomprise boric acid, sodium borate, potassium citrate, citric acid,sodium bicarbonate, TRIS, and various mixed phosphate buffers (includingcombinations of Na₂HPO₄, NaH₂PO₄, and KH₂PO₄) and mixtures thereof. Insome aspects, the one or more suitable buffers comprise 0.39 wt % sodiumacetate trihydrate and 0.17 wt % sodium citrate.

In some aspects, the solution is an aqueous pharmaceutically stableophthalmic formulation consisting of: 0.1 wt % oxymetazolinehydrochloride; 0.64 wt % sodium chloride; 0.075 wt % potassium chloride;0.048 wt % calcium chloride dihydrate; 0.03 wt % magnesium chloridehexahydrate; one or more suitable buffers; 0.5 wt % hypromellose; andoptionally hydrochloric acid; wherein the formulation has a pH rangefrom 6.3 to 6.5. In other aspects, the one or more suitable bufferscomprise boric acid, sodium borate, potassium citrate, citric acid,sodium bicarbonate, TRIS, and various mixed phosphate buffers (includingcombinations of Na₂HPO₄, NaH₂PO₄, and KH₂PO₄) and mixtures thereof. Insome aspects, the one or more suitable buffers comprise 0.39 wt % sodiumacetate trihydrate and 0.17 wt % sodium citrate.

In one aspect, the formulation comprises sodium chloride, and the amountof sodium chloride in the formulation is about 0.2 wt %, about 0.3 wt %,about 0.4 wt %, about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about0.8 wt %, about 0.9 wt %, or about 1.0 wt %.

In one aspect, the formulation comprises potassium chloride, and theamount of potassium chloride in the formulation is about 0.01 wt %,about 0.02 wt %, about 0.03 wt %, about 0.04 wt %, about 0.05 wt %,about 0.06 wt %, about 0.07 wt %, about 0.08 wt %, about 0.09 wt %,about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, or about0.5 wt %.

In one aspect, the formulation comprises calcium chloride, and theamount of calcium chloride in the formulation is about 0.01 wt %, about0.02 wt %, about 0.03 wt %, about 0.04 wt %, about 0.05 wt %, about 0.06wt %, about 0.07 wt %, about 0.08 wt %, about 0.09 wt %, about 0.1 wt %,or about 0.2 wt %.

In one aspect, the formulation comprises magnesium chloride, and theamount of magnesium chloride in the formulation is about 0.01 wt %,about 0.02 wt %, about 0.03 wt %, about 0.04 wt %, about 0.05 wt %,about 0.06 wt %, about 0.07 wt %, about 0.08 wt %, about 0.09 wt %,about 0.1 wt %, or about 0.2 wt %.

In one aspect, the formulation comprises hypromellose, and the amount ofhypromellose in the formulation is about 0.08 wt %, about 0.09 wt %,about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt%, about 1.0 wt %, or about 2.0 wt %.

In some aspects, the oxymetazoline is provided as a pharmaceuticallyacceptable salt of oxymetazoline. The term “pharmaceutically acceptablesalt” is art-recognized, and refers to relatively non-toxic, inorganicand organic acid addition salts of compositions of the present inventionor any components thereof, including without limitation, therapeuticagents, excipients, other materials and the like. Examples ofpharmaceutically acceptable salts include those derived from mineralacids, such as hydrochloric acid and sulfuric acid, and those derivedfrom organic acids, such as ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, and the like. Examples of suitable inorganicbases for the formation of salts include but are not limited to thehydroxides, carbonates, and bicarbonates of mania, sodium, lithium,potassium, calcium, magnesium, aluminum, zinc and the like. Salts canalso be formed with suitable organic bases, including those that arenon-toxic and strong enough to form such salts.

III. Composition Stability

The compositions of the present disclosure are stable. The long-termstability is an important attribute to consider when preparingophthalmologic formulations, especially those formulations that do notcontain a preservative. Various critical quality attributes must bemaintained over the shelf life of a composition in order to ensure thelong-term stability of the composition, including assay, osmolality,impurities, viscosity, weight loss, and sterility. These attributes areaffected by various factors including temperature, relative humidity,and/or pH.

Osmolality is the concentration of all solutes in a given weight ofwater and is expressed as units of either osmolality and is an attributeimportant for the maintenance of an ophthalmologic formulation. Mostsubject's eyes have an osmolality of approximately 300 mOsm, andtherefore it is important that any formulation administered to the eyeis maintained near this range, e.g., about 290 to about 365 mOsm/kg, sothat the formulation is well tolerated.

The stability of the pH of the solution is also important for comfortand safety. If elements of the ophthalmologic formulation change the pHover time, the formulation may become unstable. Also, a change in pH canlead to administration of a formulation that could damage the eye.Therefore, it is important that a desired physiological pH is maintainedacross the entire life of the formulation. Maintaining pH close toneutral and the natural pH of the eye is important for safety.

Viscosity is a quality of an ophthalmologic formulation that is criticalto maintain residence time of the formulation in the eye. It isimportant that the viscosity of the formulation is maintained over thelife of the formulation so that the viscosity is consistent and thedelivery and residence time of the active ingredient is maintained. Forexample, in one aspect the viscosity is from about 15 to about 35 cPs tomaintain residence time in the eye and eye comfort.

Unstable solutions can degrade over time to produce unwanted degradationproducts. These products can be the result of unwanted chemicalreactions involving the active ingredient, including hydrolysis andoxidation. The instability of the solution with respect to degradationproducts can lead to both toxicity as a result of the production ofthese impurities, and a lower concentration of the active ingredient dueto degradation. Unwanted degradation products includeN-(2-Aminoethyl)-2-[4-(1,1-dimethylethyl)-3-hydroxy-2,6-dimethylphenyl]acetamide,hydroxylated imidazoline derivatives, hydroxylamine, and N-oxidederivatives. Non-limiting examples of degradation products produced fromoxymetazoline degradation include:

The presence of these degradation products must therefore be limited andmonitored as a formulation ages, to prevent the potential loss ofactivity of the active ingredient and to prevent potential unwantedtoxicity derived from any degradation products that develop.

Maintenance of the sterility of the formulation is also important.Sterility testing ensures that the ophthalmologic formulation is freefrom contamination of microorganisms, which could potentially lead toinfection or other complications.

Maintenance of the water content in the formulation is important tomaintain the desired concentration of components present in theformulation, and therefore a loss of water weight will affect theconcentration of the components. Similarly, maintenance and monitoringof the degradation of components is also important because degradationproducts can also affect the concentration of the components, the pH ofthe solution, and can introduce unwanted contaminants that may pose arisk to the safety of the eye. The limit of degradation products iscritical to drug product safety, and formulation and process variablescan impact degradation products.

In some aspects, the compositions of the present disclosure are stablefor about 3 months, about 6 months, about 9 months, about 12 months,about 14 months, about 18 months, about 21 months, about 24 months,about 30 months, about 36 months, about 42 months, about 48 months,about 54 months, or about 60 months. In some aspects, the compositionsof the present disclosure are stable for about 3 months. In someaspects, the compositions of the present disclosure are stable for about6 months. In some aspects, the compositions of the present disclosureare stable for at least about 9 months. In some aspects, thecompositions of the present disclosure are stable for at least about 12months. In some aspects, the compositions of the present disclosure arestable for about 14 months. In some aspects, the compositions of thepresent disclosure are stable for at least about 18 months. In someaspects, the compositions of the present disclosure are stable for about21 months. In some aspects, the compositions of the present disclosureare stable for at least about 24 months. In some aspects, thecompositions of the present disclosure are stable for at least about 30months. In some aspects, the compositions of the present disclosure arestable for at least about 36 months. In some aspects, the compositionsof the present disclosure are stable for at least about 42 months. Insome aspects, the compositions of the present disclosure are stable forat least about 48 months. In some aspects, the compositions of thepresent disclosure are stable for at least about 54 months. In someaspects, the compositions of the present disclosure are stable for atleast about 60 months.

Stability is also affected by the environmental conditions presentduring storage. For example, ambient temperature and/or humidity canaffect long term stability of an ophthalmologic preparation. In someaspects, the compositions of the present disclosure are stable attemperature of from about 4° C. to about 30° C., about 4° C. to about25° C., about 4° C. to about 20° C., about 10° C. to about 20° C., about15° C. to about 20° C., or about 20° C. to about 30° C. In some aspects,the compositions of the present disclosure are stable at about 15° C.,about 16° C., about 17° C., about 18° C., about 19° C., about 20° C.,about 21° C., about 22° C., about 23° C., about 24° C., about 25° C.,about 26° C., about 27° C., about 28° C., about 29° C., or about 30° C.

In some aspects, the compositions of the present disclosure are stableat a relative humidity of from about 10% to about 70%, from about 20% toabout 60%, from about 30% to about 50%, from about 20% to about 80%,from about 30% to about 70%, from about 40% to about 60%. In someaspects, the compositions of the present disclosure are stable at arelative humidity of from about 10% to about 70%. In some aspects, thecompositions of the present disclosure are stable at a relative humidityof from about 40% to about 60%. In some aspects, the compositions of thepresent disclosure are stable at a relative humidity of about 10%, about20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about80%. In some aspects, the compositions of the present disclosure arestable at a relative humidity of about 10%. In some aspects, thecompositions of the present disclosure are stable at a relative humidityof about 20%. In some aspects, the compositions of the presentdisclosure are stable at a relative humidity of about 30%. In someaspects, the compositions of the present disclosure are stable at arelative humidity of about 40%. In some aspects, the compositions of thepresent disclosure are stable at a relative humidity of about 50%. Insome aspects, the compositions of the present disclosure are stable at arelative humidity of about 60%. In some aspects, the compositions of thepresent disclosure are stable at a relative humidity of about 70%. Insome aspects, the compositions of the present disclosure are stable at arelative humidity of about 80%.

IV. Methods of Treatment

The upper eyelids are normally lifted by contraction of the levatorpalpebrae superioris (levator) and Muller's (Mueller's) muscles. Ptosiscreates a tired-looking appearance that can be cosmetically undesired;in more severe instances ptosis can interfere with vision in theaffected eye(s). In addition to fatigue and age-related weakening of thelevator and Muller's muscles as underlying causes of ptosis, there are anumber of other conditions recognized to cause ptosis. For example,ptosis may also be due to a myogenic, neurogenic, aponeurotic,mechanical, or traumatic cause; it usually occurs isolated, but it maybe associated with various other conditions, like hereditary,immunological, or degenerative disorders, tumors, and infections. Themethods of the present disclosure are useful for the treatment ofptosis. In some aspects, a therapeutically effective amount ofoxymetazoline hydrochloride is delivered in an ophthalmically acceptablecarrier. In some aspects, the carrier is an emulsion, suspension, gel,ointment, or solution.

In a particular aspect, the solution is a topical ophthalmic solutionadministered as eye drops. Myogenic causes of ptosis can includediseases which may cause weakness in muscles or nerve damage, such asmyasthenia gravis and chronic progressive external ophthalmoplegia.Dystrophy or dysgenesis of the elevator and/or Muller's muscles are themost common causes of congenital ptosis. Ptosis may be caused by damageto the third cranial nerve (oculomotor nerve) which controls the muscleswhich raise the upper eyelid. Congenital neurogenic ptosis is believedto be caused by Horner syndrome (also known as Horner's syndrome), inwhich a mild ptosis due to the paresis of the Muller muscle may beassociated with ipsilateral miosis (pupillary constriction) andanhidrosis. Acquired Homer syndrome may result after trauma, neoplasticinsult, or even vascular disease. Acquired ptosis is commonly caused byaponeurotic ptosis. This can occur as a result of senescence, dehiscenceor disinsertion of the levator aponeurosis.

Moreover, chronic inflammation or intraocular surgery can lead to thesame effect. Ptosis due to trauma can ensue after an eyelid lacerationwith transection of the upper eyelid elevator muscles or disruption ofthe neural input. Other causes of ptosis include eyelid neoplasms,neurofibromas, or the cicatrization after inflammation or surgery. Mildptosis may occur with aging. It has been surprisingly found, through aprocess of evaluating a number of agents over a range of concentrationsof such agents, that certain alpha adrenergic agonists, including inparticular oxymetazoline HCl 0.1 wt %, provides a highly effectivecomposition that produces surprising treatment outcomes as measured byLeicester Peripheral Field Test (LPFT) performance. It has been foundthat this composition can be used for the treatment of ptosis, lastingfor 4-10 hours, or 6 hours in one aspect, following topicaladministration of a single drop of such agent to an affected eye.

It has been also surprisingly found, through a process of evaluating anumber of agents over a range of concentrations of such agents, thatcertain alpha adrenergic agonists, including in particular oxymetazolinehydrochloride 0.1 wt %, provides a highly effective composition thatproduces surprising treatment outcomes as measured by Marginal ReflexDistance Test (MRD-1) performance. It has been found that thiscomposition can be used for the treatment of ptosis, lasting for 4-10hours, or 6 hours, following topical administration of a single drop ofsuch agent to an affected eye. Rapid onset of the effects of theoxymetazoline hydrochloride 0.1 wt % was also found, with demonstratedimprovement of ptosis 5 minutes after administration of the compositionsof the present invention. It was also found that the MRD-1 performanceimprovement lasted for at least 6 hours after dose administration. Itwas also found that the MRD-1 performance improvement lasted for atleast 8 hours. The compounds and methods of the present invention didnot exhibit tachyphylaxis, which is a rapidly diminishing response tosuccessive doses of a drug, rendering it less effective. In someaspects, tachyphylaxis is not exhibited for six weeks. In some aspects,tachyphylaxis is not exhibited for a period of six weeks to threemonths. In some aspects, tachyphylaxis is not exhibited for a period of6 weeks, 7 weeks, 9 weeks, 10 weeks, 11 weeks, 1 months, 2 months, or 3months. In some aspects, tachyphylaxis is not exhibited during use ofthe compositions or methods of the present invention. In some aspects,tachyphylaxis is not exhibited for a period of about 1 week, about 90days, about 180 days, or about one year. In some aspects tachyphylaxisis not exhibited for a period of about 1 year, about 2 years, about 3years, about 5 years, or about 10 years.

An aspect of the invention is a method for treating ptosis in a subject.The method includes the step of topically administering an effectiveamount of oxymetazoline to the exterior surface of an eye of a subjectin need of such treatment. As used herein, “treating” means reducing,even if only temporarily, the severity of a condition or disease in asubject having such condition or disease. In one aspect the reducing iseliminating, even if only temporarily. For example, ptosis in a subjectis said to be treated in accordance with the method if the ptosis isreduced or eliminated, even if only temporarily.

The methods of the present disclosure are also related to treating othereyelid diseases or unspecific conditions whereby the condition istreated by raising the eyelid. Other conditions that may be treated bythe formulations of the present disclosure include Horner syndrome andMyasthenia gravis. The methods of the present disclosure can be used totreat other clinical conditions associated with eye, such as an eyedisorder or an eye disease. The method includes administering to atleast one eye of a subject in need of such a treatment a therapeuticallyeffective amount of a composition of the present disclosure. In someaspects, the clinical condition associated with eye includes dry eyesyndrome (e.g., keratoconjunctivitis sicca), Sjogren's syndrome,congenital alacrima, xerophthalmia (dry eye from vitamin A deficiency),keratomalacia, thyroid eye disease, ocular rosacea, eyelid disorders,meibomian gland disease, meibomian gland dysfunction, ectropion,blepharitis, blepharochalasis, sarcoidosis, stye, hordeolum, chalazion,ptosis, pterygium, eyelid edema, eyelid dermatitis, trichiasis,madarosis, dacryoadenitis, stevens-johnson syndrome, ocular graft versushost disease, dacryocystitis, conjunctivitis, keratoconjunctivitis,blepharoconjunctivitis, blepharokeratoconjunctivitis, allergicconjunctivitis, vernal conjunctivitis, conjunctival suffusion,conjunctivochalasis, subconjunctival hemorrhage, pterygium, pinguecula,chemosis, iritis, iridocyclitis, glaucoma, ocular hypertension, red eye,keratitis, scleritis, episcleritis, peripheral ulcerative keratitis,neurotrophic keratitis, neurotrophic eye disease, corneal ulcer,ulcerative keratitis, corneal abrasion, photokeratitis, ultravioletkeratitis, exposure keratitis, and corneal dystrophy.

Other conditions include post-operative inflammation following ocularsurgery (e.g. eyelid surgery, cataract surgery, corneal surgery,refractive surgery including photorefractive keratectomy, glaucomasurgery, lacrimal gland surgery, conjunctival surgery, eye musclesurgery, physical trauma, ocular conditions caused by the followingautoimmune or vascular disorders: rheumatoid arthritis, juvenilerheumatoid arthritis, ankulosing spondylitis, reiter's syndrome,enteropathic arthritis, psoriatic arthritis, discoid and systemic lupuserythematosus, multiple sclerosis, graves' disease, antiphospholipidsyndrome, sarcoidosis, wegner's granulomatosis, behcet's syndrome,polyarteritis nodosa, takayasu's arteritis, dermatomyositis, psoriasis,relapsing polychondritis, vasculitis, sickle cell-anemia, type IIdiabetes, diabetic retinopathy, and a combination thereof.

V. Dosing Frequency and Dose Escalation

According to the present invention, a subject (e.g., human) having or atrisk of having ptosis is administered any of the pharmaceuticalcompositions described herein. In some aspects, the pharmaceuticalcompositions are administered at a constant, therapeutically-effectivedose from the onset of therapy. The therapeutically-effective dose cancontain 0.1 wt % oxymetazoline HCl and be one drop per eye. In oneaspect, the dose comprises two drops of about 0.035 g/drop of a 0.1 wt %solution for a total dose of about 0.07 mg and wherein thepharmaceutical composition comprises about 0.035 mg oxymetazolinehydrochloride in each drop.

A pharmaceutical composition can be administered three times per day,twice per day, or once per day in a unit dose, wherein the total dailycomposition dose is about 0.005 g, about 0.01 g, about 0.02 g, about0.03 g, about 0.04 g, about 0.05 g, about 0.06 g, about 0.07 g, about0.08 g, about 0.09 g, or about 0.10 g. A pharmaceutical compositioncontaining oxymetazoline hydrochloride 0.1 wt % can be administeredthree times per day, twice per day, or once per day in a unit dose,wherein the total daily oxymetazoline hydrochloride dose is about 0.050mg, about 0.010 mg, about 0.020 mg, about 0.030 mg, about 0.035 mg,about 0.040 mg, about 0.050 mg, about 0.060 mg, about 0.070 mg, about0.080 mg, about 0.090 mg, about 0.1 mg about 0.14 mg or about 0.21 mg.In some aspects, the pharmaceutical composition is administered threetimes per day, twice per day, or once per day in a unit dose in eacheye. In some aspects, the total daily composition dose is about 0.07 mg,about 0.14 mg, or about 0.21 mg.

In some aspects, the formulation is administered in an amount of about0.07 mg. In some aspects, the formulation is administered on one or moreconsecutive days at a dose of one drop in a single eye for a total dailydose of about 0.035 mg. In some aspects, the formulation is administeredon one or more consecutive days at a dose of one drop in each eye for atotal daily dose of about 0.07 mg of oxymetazoline hydrochloride.

In one aspect, the pharmaceutical composition is administered once dailyto one or both eyes. In one aspect, the pharmaceutical composition isadministered in the morning. In one aspect, the pharmaceuticalcomposition is administered in the afternoon. In one aspect, thepharmaceutical composition is administered in the evening. In oneaspect, the pharmaceutical composition is administered more than 4 hoursbefore bedtime. In some aspects, a pharmaceutical composition containingoxymetazoline or a pharmaceutically acceptable salt thereof, isadministered twice per day or once per day in a unit dose comprisingabout 0.015 mg, about 0.035 mg, or about 0.07 mg. In some aspects, asingle drop is administered to each eye during each dose administration.In some aspects, a single drop is administered to only one eye duringeach dose administration.

VI. Pharmaceutical Compositions

Another aspect of the present disclosure relates to a pharmaceuticalcomposition comprising oxymetazoline hydrochloride. For ophthalmicapplication, preferably solutions are prepared using a physiologicalsaline solution as the vehicle. The pH of such ophthalmic solutionsshould preferably be maintained from 4.5 and 8.0 with an appropriatebuffer system. Ideally, the pH of such solutions is maintained from 6.3and 6.5. The formulations can also contain conventional,pharmaceutically acceptable stabilizers and surfactants. Tonicityadjustors can be added as needed or convenient. They include, but arenot limited to, salts, particularly sodium chloride, potassium chloride,mannitol and glycerin, or any other suitable ophthalmically acceptabletonicity adjustor. Various buffers and means for adjusting pH can beused so long as the resulting preparation is ophthalmically acceptable.Accordingly, buffers include acetate buffers, citrate buffers, phosphatebuffers and borate buffers. In some aspects, the pharmaceuticalcomposition is an ophthalmic dosage form. The present disclosure is notlimited to a particular ophthalmic dosage form, and any dosage formcapable of delivering oxymetazoline hydrochloride to a patient issuitable for the present invention, so long as the dosage form achievespharmacokinetic and therapeutic effects described in the presentdisclosure.

In one aspect, the formulation does not contain preservative(s).

In some aspects, the pharmaceutical composition comprises an adsorbent,antioxidant, buffering agent, and/or diluent.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium ascorbate, sodiumbisulfite, sodium citrate, sodium formaldehyde sulfoxylate and sodiummetabisulfite and other materials known to one of ordinary skill in theart.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dihydrate and othermaterials known to one of ordinary skill in the art.

VII. Leicester Peripheral Field Test (LPFT)

The efficacy of the compositions of the present disclosure can beevaluated using a variety of tests to assess patient improvement. Insome aspects, a Leicester Peripheral Field Test (LPFT) is used to assesspatient improvement outcomes. In some aspects, a Leicester PeripheralField Test (LPFT) is used for assessment, and a Leicester PeripheralField Test (LPFT) mean score and a Leicester Peripheral Field Test(LPFT) median score is determined. In some aspects, the LeicesterPeripheral Field Test (LPFT) mean score is increased by about 5-10points after about 0.1-16 hours. In some aspects, the LeicesterPeripheral Field Test (LPFT) mean score is increased by about 5.2 pointsor about 6.3 points after about 0.1-16 hours. In some aspects, theLeicester Peripheral Field Test (LPFT) mean score is increased by about5.2 points or about 6.3 points after about 6 hours. In some aspects, theLeicester Peripheral Field Test (LPFT) mean score is increased by about5-10 points after about 10-15 days. In some aspects, the LeicesterPeripheral Field Test (LPFT) mean score is increased by about 6 pointsto about 8 points after about 10-15 days. In some aspects, the LeicesterPeripheral Field Test (LPFT) mean score is increased by about 6.4 pointsor about 7.7 points after about 10-15 days. In some aspects, theLeicester Peripheral Field Test (LPFT) mean score is increased by about6.4 points or about 7.7 points after about 14 days.

In some aspects, the Leicester Peripheral Field Test (LPFT) mean scoreis increased by about 5-10 points after about 0.1-16 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 5-10 points after about 5 to about 10 minutes. Insome aspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 5.2 points or about 6.3 points after about 0.1-16hours. In some aspects, the Leicester Peripheral Field Test (LPFT) meanscore is increased by about 5.2 points or about 6.3 points after about 6hours. In some aspects, the Leicester Peripheral Field Test (LPFT) meanscore is increased by about 5.2 points after about 6 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 6.3 points after about 6 hours. In some aspects, theLeicester Peripheral Field Test (LPFT) mean score is increased by about7.7 points after about 2 hours. In some aspects, the LeicesterPeripheral Field Test (LPFT) mean score is increased by about 6.4 pointsafter about 2 hours. In some aspects, the Leicester Peripheral FieldTest (LPFT) mean score is increased by about 5-10 points after about10-15 days. In some aspects, the Leicester Peripheral Field Test (LPFT)mean score is increased by about 6 points to about 8 points after about10-15 days. In some aspects, the Leicester Peripheral Field Test (LPFT)mean score is increased by about 6.4 points or about 7.7 points afterabout 10-15 days. In some aspects, the Leicester Peripheral Field Test(LPFT) mean score is increased by about 6.4 points or about 7.7 pointsafter about 14 days.

In some aspects, the Leicester Peripheral Field Test (LPFT) median scoreis increased by about 5-10 points after about 0.1-16 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) median score isincreased by about 7 points after about 0.1-16 hours. In some aspects, aLeicester Peripheral Field Test (LPFT) is used for assessment, and aLeicester Peripheral Field Test (LPFT) mean score and a LeicesterPeripheral Field Test (LPFT) median score is determined. In someaspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 5-10 points after about 2 hours or after about 6hours. In some aspects, the Leicester Peripheral Field Test (LPFT)median score is increased by about 7 points after about 6 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) median score isincreased by about 5-10 points after about 10-15 days. In some aspects,the Leicester Peripheral Field Test (LPFT) median score is increased byabout 9 points after about 10-15 days. In some aspects, the LeicesterPeripheral Field Test (LPFT) median score is increased by about 9 pointsafter about 14 days.

In some aspects, the Leicester Peripheral Field Test (LPFT) mean scoreis increased by about 5-20 points after about 1-9 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 5-15 points after about 0.1-16 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 10-15 points after about 0.1-16 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 5-15 points after about 2 to about 6 hours. In someaspects, the Leicester Peripheral Field Test (LPFT) mean score isincreased by about 5-15 points after about 1-14 days. In some aspects,the Leicester Peripheral Field Test (LPFT) mean score is increased byabout 5-10 points after about 1 day. In some aspects, the LeicesterPeripheral Field Test (LPFT) mean score is increased by about 5-10points after about 14 days. In some aspects, the Leicester PeripheralField Test (LPFT) mean score is increased by about 5-10 points afterabout 14 days. In some aspects, the Leicester Peripheral Field Test(LPFT) mean score is increased by about 5-10 points after about 0.1-16hours.

In some aspects, the Leicester Peripheral Field Test (LPFT) mean scoreis increased by about 1, by about 2, by about 3, by about 4, by about 5,by about 6, by about 7, by about 8, by about 9, by about 10, by about11, by about 12, by about 13, by about 14, by about 15, by about 16, byabout 17, by about 18, by about 19, or by about 20 points after about0.1-16 hours. In some aspects, the Leicester Peripheral Field Test(LPFT) mean score is increased by about 1, by about 2, by about 3, byabout 4, by about 5, by about 6, by about 7, by about 8, by about 9, byabout 10, by about 11, by about 12, by about 13, by about 14, by about15, by about 16, by about 17, by about 18, by about 19, or by about 20points after about 6 hours. In some aspects, the Leicester PeripheralField Test (LPFT) mean score is increased by about 1, by about 2, byabout 3, by about 4, by about 5, by about 6, by about 7, by about 8, byabout 9, by about 10, by about 11, by about 12, by about 13, by about14, by about 15, by about 16, by about 17, by about 18, by about 19, orby about 20 points after about 10-15 days. In some aspects, theLeicester Peripheral Field Test (LPFT) mean score is increased by about1, by about 2, by about 3, by about 4, by about 5, by about 6, by about7, by about 8, by about 9, by about 10, by about 11, by about 12, byabout 13, by about 14, by about 15, by about 16, by about 17, by about18, by about 19, or by about 20, points after about 14 days.

In some aspects, the Leicester Peripheral Field Test (LPFT) median scoreis increased by about 1, by about 2, by about 3, by about 4, by about 5,by about 6, by about 7, by about 8, by about 9, by about 10, by about11, by about 12, by about 13, by about 14, by about 15, by about 16, byabout 17, by about 18, by about 19, or by about 20 points after about0.1-16 hours. In some aspects, the Leicester Peripheral Field Test(LPFT) median score is increased by about 1, by about 2, by about 3, byabout 4, by about 5, by about 6, by about 7, by about 8, by about 9, byabout 10, by about 11, by about 12, by about 13, by about 14, by about15, by about 16, by about 17, by about 18, by about 19, or by about 20points after about 6 hours. In some aspects, the Leicester PeripheralField Test (LPFT) median score is increased by about 1, by about 2, byabout 3, by about 4, by about 5, by about 6, by about 7, by about 8, byabout 9, by about 10, by about 11, by about 12, by about 13, by about14, by about 15, by about 16, by about 17, by about 18, by about 19, orby about 20 points after about 10-15 days. In some aspects, theLeicester Peripheral Field Test (LPFT) median score is increased byabout 1, by about 2, by about 3, by about 4, by about 5, by about 6, byabout 7, by about 8, by about 9, by about 10, by about 11, by about 12,by about 13, by about 14, by about 15, by about 16, by about 17, byabout 18, by about 19, or by about 20 points after about 14 days.

In some aspects, the Leicester Peripheral Field Test (LPFT) median scoreremains elevated for a period of about 10 minutes, about 20 minutes,about 1 hour, about 6 hours, about 8 hours, about 12 hours, or about 24hours.

VIII. Marginal Reflex Distance 1 (MRD-1) Test

The Marginal Reflex Distance 1 (MRD-1) test is conducted usingphotographic measurement to assess the distance from the centralpupillary light reflex to the central margin of the upper lid. Externaldigital photographs are used to measure MRD-1. Measurements are takenbased on the distance from the central pupillary light reflex to thecentral margin of the upper lid, ≤2 mm (no visible central pupillarylight reflex defaults to 0). The MRD-1 test is useful to assess efficacyof treatment.

In some aspects, a Marginal Reflex Distance 1 Test (MRD-1) is used toassess patient improvement outcomes. In some aspects, a Marginal ReflexDistance 1 Test (MRD-1) is used for assessment, and a Marginal ReflexDistance 1 Test (MRD-1) mean score and a Marginal Reflex Distance 1 Test(MRD-1) median score is determined. In some aspects, a Marginal ReflexDistance 1 Test (MRD-1) is conducted, and whereby the mean score isincreased by about 0.2-1.0 points after about 1-10 minutes. In someaspects, the Marginal Reflex Distance 1 Test (MRD-1) mean score isincreased by about 0.2-1.0 points after about 5 minutes. In someaspects, the Marginal Reflex Distance 1 Test (MRD-1) mean score isincreased by about 0.6 points after about 5 minutes. In some aspects,the Marginal Reflex Distance 1 Test (MRD-1) mean score is increased byabout 0.5-1.5 points after about 10-20 minutes. In some aspects, theMarginal Reflex Distance 1 Test (MRD-1) mean score is increased by about0.5-1.5 points after about 15 minutes. In some aspects, the MarginalReflex Distance 1 Test (MRD-1) mean score is increased by about 0.9points after about 15 minutes.

In some aspects, the Marginal Reflex Distance 1 Test (MRD-1) mean scoreis increased by about 0.5-1.5 points after about 5 minutes to about 16hours. In some aspects, the Marginal Reflex Distance 1 Test (MRD-1) meanscore is increased by about 0.5-1.5 points after about 15 minutes toabout 16 hours. In some aspects, the Marginal Reflex Distance 1 Test(MRD-1) mean score is increased by about 0.5-1.5 points after about 15minutes. In some aspects, the mean score is increased by about 0.2-1.0points after about 5 minutes to about 16 hours. In some aspects, themean score is increased by about 0.5-1.5 points after about 5 minutes toabout 42 days.

In some aspects, the Marginal Reflex Distance 1 Test (MRD-1) mean scoreis increased by about 1.5 points, by about 1.4 points, by about 1.3points, by about 1.2 points, by about 1.1 points, by about 1.0 point, byabout 0.9 points, by about 0.8 points, by about 0.7 points, by about 0.6points, by about 0.5 points, by about 0.4 points, or by about 0.3 pointsafter about 5 minutes to about 16 hours. In some aspects, the MarginalReflex Distance 1 Test (MRD-1) mean score is increased by about 1.5points, by about 1.4 points, by about 1.3 points, by about 1.2 points,by about 1.1 points, by about 1.0 point, by about 0.9 points, by about0.8 points, by about 0.7 points, by about 0.6 points, by about 0.5points, by about 0.4 points, or by about 0.3 points after about 5minutes. In some aspects, the Marginal Reflex Distance 1 Test (MRD-1)mean score is increased by about 1.5 points, by about 1.4 points, byabout 1.3 points, by about 1.2 points, by about 1.1 points, by about 1.0point, by about 0.9 points, by about 0.8 points, by about 0.7 points, byabout 0.6 points, by about 0.5 points, by about 0.4 points, or by about0.3 points after about 15 minutes. In some aspects, the Marginal ReflexDistance 1 Test (MRD-1) mean score is increased by about 1.5 points, byabout 1.4 points, by about 1.3 points, by about 1.2 points, by about 1.1points, by about 1.0 point, by about 0.9 points, by about 0.8 points, byabout 0.7 points, by about 0.6 points, by about 0.5 points, by about 0.4points, or by about 0.3 points after about 16 hours.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) mean score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 1-20 minutes. In some aspects, the MarginalReflex Distance 1 (MRD-1) mean score is increased by about 0.1, by about0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, by about0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, by about1.7, by about 1.8, by about 1.9, or by about 2.0 points after about 5minutes.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) mean score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 10-20 minutes. In some aspects, theMarginal Reflex Distance 1 (MRD-1) mean score is increased by about 0.1,by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, byabout 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, byabout 1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, byabout 1.7, by about 1.8, by about 1.9, or by about 2.0 points afterabout 15 minutes.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) mean score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 2-12 hours. In some aspects, the MarginalReflex Distance 1 (MRD-1) mean score is increased by about 0.1, by about0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, by about0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, by about1.7, by about 1.8, by about 1.9, or by about 2.0 points after about 2hours. In some aspects, the Marginal Reflex Distance 1 (MRD-1) meanscore is increased by about 0.1, by about 0.2, by about 0.3, by about0.4, by about 0.5, by about 0.6, by about 0.7, by about 0.8, by about0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about1.9, or by about 2.0 points after about 6 hours.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) mean score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 5-20 days. In some aspects, the MarginalReflex Distance 1 (MRD-1) mean score is increased by about 0.1, by about0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, by about0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, by about1.7, by about 1.8, by about 1.9, or by about 2.0 points after about 14days.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) mean score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 30-60 days. In some aspects, the MarginalReflex Distance 1 (MRD-1) mean score is increased by about 0.1, by about0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, by about0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, by about1.7, by about 1.8, by about 1.9, or by about 2.0 points after about 42days.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) median score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 1-20 minutes. In some aspects, the MarginalReflex Distance 1 (MRD-1) median score is increased by about 0.1, byabout 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, byabout 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, byabout 1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, byabout 1.7, by about 1.8, by about 1.9, or by about 2.0 points afterabout 0.1-16 hours, e.g., 8 hours. In some aspects, the Marginal ReflexDistance 1 (MRD-1) median score is increased by about 0.1, by about 0.2,by about 0.3, by about 0.4, by about 0.5, by about 0.6, by about 0.7, byabout 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, byabout 1.3, by about 1.4, by about 1.5, by about 1.6, by about 1.7, byabout 1.8, by about 1.9, or by about 2.0 points after about 5 minutes.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) median score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 10-20 minutes. In some aspects, theMarginal Reflex Distance 1 (MRD-1) median score is increased by about0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about1.1, by about 1.2, by about 1.3, by about 1.4, by about 1.5, by about1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 pointsafter about 15 minutes.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) median score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 2-12 hours. In some aspects, the MarginalReflex Distance 1 (MRD-1) median score is increased by about 0.1, byabout 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, byabout 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, byabout 1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, byabout 1.7, by about 1.8, by about 1.9, or by about 2.0 points afterabout 2 hours. In some aspects, the Marginal Reflex Distance 1 (MRD-1)median score is increased by about 0.1, by about 0.2, by about 0.3, byabout 0.4, by about 0.5, by about 0.6, by about 0.7, by about 0.8, byabout 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, byabout 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, byabout 1.9, or by about 2.0 points after about 6 hours.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) median score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 5-20 days. In some aspects, the MarginalReflex Distance 1 (MRD-1) median score is increased by about 0.1, byabout 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, byabout 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, byabout 1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, byabout 1.7, by about 1.8, by about 1.9, or by about 2.0 points afterabout 14 days.

In some aspects, the Marginal Reflex Distance 1 (MRD-1) median score isincreased by about 0.1, by about 0.2, by about 0.3, by about 0.4, byabout 0.5, by about 0.6, by about 0.7, by about 0.8, by about 0.9, byabout 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1.4, byabout 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or byabout 2.0 points after about 30-60 days. In some aspects, the MarginalReflex Distance 1 (MRD-1) median score is increased by about 0.1, byabout 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0.6, byabout 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, byabout 1.2, by about 1.3, by about 1.4, by about 1.5, by about 1.6, byabout 1.7, by about 1.8, by about 1.9, or by about 2.0 points afterabout 42 days.

IX. Pharmacokinetics

In one aspect, the dose comprises two drops of about 0.035 g/drop of a0.1 wt % composition for a total dose of about 0.070 mg and wherein thepharmaceutical composition comprises about 0.035 mg oxymetazolinehydrochloride in each drop. In another aspect, each drop of ophthalmicsolution contains 0.035 mg (0.1% oxymetazoline hydrochloride, which isequivalent to 0.031 mg (0.088% of oxymetazoline free base equivalents).

The compositions and methods of the present disclosure are useful forminimizing a patient's systemic exposure to oxymetazoline hydrochloride.In some aspects, a mean AUC_(0-∞) of the pharmaceutical compositionafter a single-dose administration is from about 300 to about 700pg·h/mL. In some aspects, a mean AUC_(0-∞) of the pharmaceuticalcomposition after a single-dose administration is about 468 pg·h/mL.

In some aspects, the T_(max) of the pharmaceutical composition after asingle-dose administration is from about 0.5 to about 6 hours. In someaspects, the T_(max) of the pharmaceutical composition after asingle-dose administration is about 2-4 hours. In some aspects, theT_(max) of the pharmaceutical composition after a single-doseadministration is about 0.5-4 hours. In some aspects, the T_(max) of thepharmaceutical composition after a single-dose administration is about 2hours.

In some aspects, the mean T_(max) of the pharmaceutical compositionafter single dose administration to a patient is from about 0.5 hours toabout 12 hours, from about 0.5 hours to about 10 hours, from about 0.5hours to about 8 hours, from about 0.5 hours to about 6 hours, fromabout 6 hours to about 12 hours, from about 6 hours to about 10 hours,from about 6 hours to about 8 hours, from about 7 hours to about 12hours, from about 7 hours to about 10 hours, from about 7 hours to about8 hours, from about 8 hours to about 12 hours, from about 8 hours toabout 10 hours, from about 9 hours to about 12 hours, from about 9 hoursto about 10 hours, or from about 10 hours to about 12 hours. In someaspects, the mean T_(max) of the pharmaceutical composition is fromabout 0 hours to about 6 hours, from about 1 hours to about 6 hours,from about 1 hours to about 5 hours, from about 2 hours to about 5hours, from about 2 hours to about 4 hours, or from about 2 hours toabout 3 hours. In one aspect, the mean T_(max) of the pharmaceuticalcomposition is about 2.5 hours. In some aspects, the median T_(max) ofthe pharmaceutical composition is about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, or about 10 hours.

In some aspects, the mean C_(max) of the pharmaceutical compositionafter a single-dose administration is from about 25 pg/ml to about 35pg/ml. In some aspects, the mean C_(max) of the pharmaceuticalcomposition after a single-dose administration is about 28-32 pg/ml. Insome aspects, the mean C_(max) of the pharmaceutical composition after asingle-dose administration is about 30.5 pg/ml.

In one aspect, the dose comprises two drops of about 0.035 g/drop of a0.1 wt % composition for a total of about 0.070 g and wherein thepharmaceutical composition comprises about 0.035 mg oxymetazolinehydrochloride in each drop. In some aspects, the mean C_(max) of thepharmaceutical composition after a single-dose administration to apatient is from about 10 pg/ml to about 40 pg/ml, from about 12 pg/ml toabout 38 pg/ml, from about 14 pg/ml to about 36 pg/ml, from about 16pg/ml to about 34 pg/ml, from about 18 pg/ml to about 32 pg/ml, or fromabout 20 pg/ml to about 30 pg/ml. In some aspects, the mean C_(max) ofthe pharmaceutical composition after a single-dose administration isabout 20 pg/ml, about 21 pg/ml, about 22 pg/ml, about 22 pg/ml, about 23pg/ml, about 24 pg/ml, about 25 pg/ml, about 26 pg/ml, about 27 pg/ml,about 28 pg/ml, about 29 pg/ml, about 30 pg/ml, about 31 pg/ml, about 32pg/ml, about 33 pg/ml, about 34 pg/ml, about 35 pg/ml, about 36 pg/ml,about 37 pg/ml, about 38 pg/ml, about 39 pg/ml, or about 40 pg/ml. Insome aspects, the mean C_(max) of the pharmaceutical composition after asingle-dose administration is from about 25 pg/ml to about 35 pg/ml. Insome aspects, the mean C_(max) of the pharmaceutical composition after asingle-dose administration is about 28-32 pg/ml. In some aspects, themean C_(max) of the pharmaceutical composition after a single-doseadministration is about 30.5 pg/ml. In some aspects, the mean C_(max) ofthe pharmaceutical composition after a single-dose administration isabout 30.5 pg/ml, and the geometric mean Cmax is about 28.3 pg/mL.

In some aspects, the mean area under the plasma concentration-time curve(AUC_(0-∞)) is measured. In some aspects, a mean AUC_(0-∞) of thepharmaceutical composition after a single-dose administration is fromabout 0 pg·h/mL to about 800 pg·h/mL, from about 50 pg·h/mL to about 800pg·h/mL, from about 50 pg·h/mL to about 750 pg·h/mL, from about 100pg·h/mL to about 750 pg·h/mL, from about 100 pg·h/mL to about 700pg·h/mL, from about 150 pg·h/mL to about 700 pg·h/mL, from about 150pg·h/mL to about 650 pg·h/mL, from about 200 pg·h/mL to about 650pg·h/mL, from about 200 pg·h/mL to about 600 pg·h/mL, from about 250pg·h/mL to about 600 pg·h/mL, from about 250 pg·h/mL to about 550pg·h/mL, from about 300 pg·h/mL to about 550 pg·h/mL, from about 300pg·h/mL to about 500 pg·h/mL, from about 350 pg·h/mL to about 500pg·h/mL, from about 400 pg·h/mL to about 500 pg·h/mL, or from about 420pg·h/mL to about 480 pg·h/mL. In some aspects, a mean AUC_(0-∞) of thepharmaceutical composition after a single-dose administration is about468 pg·h/mL.

In some aspects, the geometric mean AUC_(0-∞) of the pharmaceuticalcomposition after a single-dose administration is from about 0 pg·h/mLto about 800 pg·h/mL, from about 50 pg·h/mL to about 800 pg·h/mL, fromabout 50 pg·h/mL to about 750 pg·h/mL, from about 100 pg·h/mL to about750 pg·h/mL, from about 100 pg·h/mL to about 700 pg·h/mL, from about 150pg·h/mL to about 700 pg·h/mL, from about 150 pg·h/mL to about 650pg·h/mL, from about 200 pg·h/mL to about 650 pg·h/mL, from about 200pg·h/mL to about 600 pg·h/mL, from about 250 pg·h/mL to about 600pg·h/mL, from about 250 pg·h/mL to about 550 pg·h/mL, from about 300pg·h/mL to about 550 pg·h/mL, from about 300 pg·h/mL to about 500pg·h/mL, from about 350 pg·h/mL to about 500 pg·h/mL, from about 400pg·h/mL to about 500 pg·h/mL, or from about 420 pg·h/mL to about 480pg·h/mL. In some aspects, the geometric mean AUC_(0-∞) of thepharmaceutical composition after a single-dose administration is about439 pg·h/mL.

X. Packaging

The storage format and packaging of a formulation is also important tomaintain and deliver consistent product. The packaging methods of thepresent disclosure can involve the use of a single unit-dose containerformed from clear, low-density polyethylene (LDPE) resin. In someaspects, the single-use containers are formed by a blow/fill/seal(“B/F/S” or “BFS”) process. In some aspects, the BFS process isperformed in an aseptic environment. The BFS process is a process wherethe container is formed, filled, and sealed in one continuous, automatedsystem, wherein contents are kept sterile. The BFS vials arecontinuously produced on a machine that extrudes the plastic resin athigh temperature, rendering the resin sterile. The pellets feed from thehopper at the top of the BFS machine into the extruder via gravity. Theextruder heats the resin pellets to about 170° C. to about 230° C.,melting the plastic granulate to produce a sterile, extruded plastictube (parison). The process begins by melting and extruding the lowdensity polyethylene (LDPE) resin to form a parison (a hollow tubularform of the hot resin). Then the seal molds close, sealing the vials,and the molds release the filled and sealed vials. The entire process isconducted without human intervention, thus reducing the risk ofcontamination. The BFS vials can be filled upside down to ensureconsistent filling and sealed to form a “card” containing multiplevials. Sterile packaging techniques are important when the content doesnot contain preservatives or anti-microbial agents. In some aspects, theBFS vial has a volume of about 0.1 mL, about 0.2 mL, about 0.3 mL, about0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about0.9 mL, or about 1.0 mL. In some aspects, the BFS vial has a volume ofabout 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL,about 7 mL, about 8 mL, about 9 mL, or about 10 mL. In some aspects, theBFS vial has a volume of about 0.5 mL. In some aspects, the BFS vial hasa volume of 0.34 mL.

After BFS packaging, the containers can be enclosed in a foil laminatepouch for individual packaging, and/or enclosed in a child-resistantzipper bag to prevent unwanted access. Pharmaceuticals generally requireproduct packaging compliant with government regulations to includechild-resistant features to prevent young children, e.g., age 5 oryounger, from gaining access to products that could cause seriousillness or injury. Alternatively, the containers can be enclosed in achild-resistant foil laminate pouch. The child-resistant pouchingmaterials can comprise PET, aluminum foil, and/or sealant that canprovide puncture resistance, machinability, integrity, and childresistance.

The present disclosure is further illustrated by the following exampleswhich should not be construed as further limiting. The contents of allreferences cited throughout this application are expressly incorporatedherein by reference.

EXAMPLES Example 1 Formulation

The oxymetazoline hydrochloride ophthalmic solution, 0.1 wt %, wasmanufactured at a batch size of 200 kg. The batch formula for the drugproduct is provided in Table 1.

TABLE 1 Batch Formula for Oxymetazoline HCl Ophthalmic Solution, 0.1 wt% Quan- tity Quality Quantity (mg/ Stan- per Quantity dosage Componentdard Function batch (mg/mL) unit) Oxymetazoline USP Active  200.00 g*1.00 0.34 Hydrochloride Sodium USP Excipient 1280.00 g 6.40 2.18Chloride Potassium USP Excipient  150.00 g 0.75 0.26 Chloride CalciumUSP Excipient  96.00 g 0.48 0.16 Chloride, Dihydrate Magnesium USPExcipient  60.00 g 0.30 0.10 Chloride Hexahydrate Sodium USP Excipient 780.00 g 3.90 1.33 Acetate Trihydrate Sodium Citrate NF Excipient 340.00 g 1.70 0.58 Hypromellose** USP Excipient 1000.00 g 5.00 1.70(Methocel E4M) Hydrochloric NF pH    25 mL To To Acid Adjuster adjustadjust pH to pH to 6.3-6.5 6.3-6.5 Water for USP Diluent QS to QS QS toInjection 200 kg 0.34 mL Nitrogen NF Filling N/A N/A N/A (sterile andfiltered) Support Gas *Adjusted based on Assay value **Adjust tocompensate for a 5 kg purge

Formulation enhancements were pursued in an attempt to improve theoverall absorption of oxymetazoline within the eye, without the use ofpreservatives. The vehicle formulation is a balanced salt solutionintended for eye irrigation that is made to a physiological pH andisotonic salt concentration. Addition of the excipient hypromellose,which is a viscosity modifier, helps add residence time in the eye, aswell as enhance eye comfort. Eight development batches were tested usingeither Hypromellose (HPMC) or Sodium Carboxymethyl-cellulose (NA CMC).The effect of this change on pH was determined as well. Stabilitystudies were conducted at 25° C.±2° C./40% RH, 40° C.±2° C./NMT 25% RH,and 55° C./Ambient RH. The compositions and results of these tests,including 3-month stability test data, can be seen in Table 2 and Table3 below:

TABLE 2 Composition (% w/w) of the Eight Development Batches (batchsizes ~91-172 g) Lot EPS- Lot EPS- Lot EPS- Lot EPS- Lot EPS- Lot EPS-Lot EPS- Lot EPS- Ingredient 352-057 352-059 352-060 352-061 352-062352-065 357-036 357-039 Sodium  0.64%  0.64%  0.64%  0.64%  0.64%  0.64% 0.64%  0.64% Chloride Potassium 0.075% 0.075% 0.075% 0.075% 0.075%0.075% 0.075% 0.075% Chloride Calcium 0.048% 0.048% 0.048% 0.048% 0.048%0.048% 0.048% 0.048% Chloride Magnesium 0.030% 0.030% 0.030% 0.030%0.030% 0.030% 0.030% 0.030% Chloride Sodium acetate  0.39%  0.39%  0.39% 0.39%  0.39%  0.39%  0.39%  0.39% Sodium citrate  0.17%  0.17%  0.17% 0.17%  0.17%  0.17%  0.17%  0.17% HPMC —  1.0% —  0.5% — — — —(Hypromellose) Sodium  1.0% —  0.5% —  0.25%  0.25%  0.25%  0.25%Carboxymethyl- cellulose PH 7.2 7.2 7.2 7.2 5.5 6.0 6.5 7.0 Water forq.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Injection

TABLE 3 Initial Data on the Eight Developmental Batches (batchsize~91-172 g) Concentration of Concentration of OxymetazolineOxymetazoline (mg/mL) (mg/mL) 3-Month 3-Month Concentration of StabilityTest at Stability Test at Oxymetazoline Osmolality 25° C. ± 2° C./40%40° C. ± 2° C./NMT Formulation ID (mg/mL) pH (mOsm/kg) RH 25% RHEPS-352-057 (1% Na 0.99 6.6 326 0.99 0.97 CMC) EPS-352-059 (1% 0.90 6.5314 0.94 0.91 HPMC) EPS-352-060 (0.5% 0.99 6.5 313 0.98 0.99 Na CMC)EPS-352-061 (0.5% 0.95 6.5 308 0.96 0.95 HPMC) EPS-352-062 (0.25% 0.975.6 301 0.98 1.00 Na CMC; pH 5.5) EPS-352-065 (0.25% 0.99 5.8 309 0.991.00 Na CMC; pH 6.0) EPS-357-036 (0.25% 0.97 6.0 302 0.98 0.95 Na CMC;pH 6.5) EPS-357-039 (0.25% 1.00 6.6 305 0.99 0.97 Na CMC; pH 7.0)

Example 2 PK Analysis

The following pharmacokinetic data was generated based on a single dropdose in each eye, each drop containing approximately 0.035 mg ofoxymetazoline HCl, for a total of 0.07 mg oxymetazoline HCl.

Parameters C_(max), AUC_(0-∞), and T_(max) were assessed based on a testpopulation of 24 patients.

A study was conducted to determine mean plasma oxymetazolineconcentrations following single-dose administration of Oxymetazoline HClOphthalmic Solution, 0.1 wt %. The results of the study are detailed inFIG. 1, Table 4, and Table 5.

TABLE 4 Summary of Pharmacokinetic Parameters Following OcularAdministration of Oxymetazoline to Healthy Male and Female Volunteers,PK Study Test Parameter n Mean SD CV % Geometric Mean tmax(h)^(a) 232.00 (0.500-12.0) — Cmax (pg/mL) 23 30.5 12.7 41.8 28.3184 AUC0-tldc 23400 188 47.1 367.5829 (h*pg/mL) AUCinf 19 468 214 45.7 438.9934(h*pg/mL) AUC % extrap 21 12.4 5.41 43.7 — kel (h-1) 21 0.0841 0.019022.6 — t½ (h)^(b) 21 8.25 — — — Treatment A: one drop of oxymetazolineHCl (ophthalmic solution, 0.1 wt %) to each eye (Test) Note: PKparameters are presented as arithmetic mean, standard deviation (SD),and coefficient of variation (CV %) unless otherwise noted. AUCinfvalues with extrapolation >20% were excluded from summary statistics.^(a)tmax is presented as median (min-max) ^(b)t½ is presented asharmonic mean

TABLE 5 Summary of Oxymetazoline Concentration-Time Data FollowingSingle-Dose Administration of Oxymetazoline HCl ophthalmic Solution,0.1%; Treatment A Mean Min Median Treatment Time (h) n (pg/mL) SD(pg/mL) CV % (pg/mL) (pg/mL) Max (pg/mL) A 0.00 23 0.00 0.00 NC 0.000.00 0.00 0.17 23 11.6 6.45 55.4 4.64 1.11 29.4 0.33 23 16.4 7.51 45.84.44 14.1 32.5 0.50 73 18.8 7.02 37.4 8.73 18.1 33.5 0.75 23 19.7 7.0535.7 9.91 17.9 34.8 1.00 23 20.2 7.90 39.1 9.37 17.6 39.0 1.50 23 23.310.8 46.4 7.15 21.8 54.7 2.00 23 23.0 8.27 35.9 7.82 23.8 48.6 3.00 2324.4 9.75 37.9 8.54 23.6 50.0 4.00 23 25.8 12.3 47.7 9.87 21.5 51.8 6.0023 22.7 11.7 51.4 9.12 17.9 58.4 8.00 23 19.7 10.2 51.5 9.01 18.3 50.612.00 23 13.8 7.42 53.9 6.40 12.6 39.0 16.00 23 11.3 6.88 60.7 4.36 10.135.2 24.00 23 6.37 4.75 74,5 0.00 5.76 21.9 30.00 23 3.36 3.44 102 0.003.36 12.9 36.00 23 1.21 2.35 195 0.00 0.00 9.01

Example 3 Phase 3 Data, Study 1

Study 1:

This Study was a multicenter, randomized, double-masked,placebo-controlled, Phase 3 study of the safety and efficacy of once perday dosing (QD) treatment (one drop per eye) with oxymetazolinehydrochloride ophthalmic solution, 0.1% compared to Vehicle in subjectswith acquired ptosis. A total of 140 subjects were randomized in anapproximate 2:1 ratio: oxymetazoline hydrochloride 0.1 wt % QD (N=94);Vehicle (N=46) at 16 sites. Oxymetazoline hydrochloride was administeredtopically for 42 days (6 weeks). The study was conducted in 2 periods;Period 1 (safety and efficacy) was 2 weeks in duration, and Period 2(extended safety and comfort) was 4 weeks in duration. The mean age ofthe subjects was 64.2 years.

3.2 Efficacy

Efficacy was assessed with the LPFT (primary) and photographicmeasurement of MRD-1. The primary efficacy endpoints were ordered in ahierarchy to compare oxymetazoline hydrochloride against vehicle on themean increase from baseline (Day 1 Hour 0) in the number of points seenon the top 4 rows of the LPFT in the study eye at:

-   -   1. Hour 6 on Day 1    -   2. Hour 2 on Day 14        This study has been completed and the results are presented        below. The increases at both time points in the number of points        seen in the superior visual field (change in LPFT) in the        oxymetazoline hydrochloride group compared to the Vehicle group        were statistically significant, showing that the improvement in        the superior visual field was evident at 6 hours post-dose on        Day 1 and 2 hours post-dose on Day 14, Table 6. The mean change        from baseline for the visual field data at time points Day 14,        hour 6, Day 14, hour 8, and Day 42 can be seen in Table 7.

TABLE 6 Observed and Change from Baseline in Mean Points Seen inSuperior Visual Field on LPFT in the Study Eye at Primary Efficacy TimePoints (ITT Population), Study 1 Mean Difference, Points SeenP-Value^(a) in Superior Visual Field [95% CI] Test Vehicle P-Value^(b)Parameter N = 94 N = 46 Test vs Vehicle Mean points at baseline   17(4.41)   1 (5.21) (SD) Mean points at primary efficacy time points N 9446 Day 1, Hour 6, observed 22.2 (6.18) 18.4 (6.01) mean (SD) Mean changefrom  5.2 (5.97)  1.5 (3.93) 3.67, <0.0001^(a), baseline (SD) [2.00,5.34] 0.0002^(b) N 91 46 Day 14, Hour 2, observed 23.4 (5.60) 19.1(6.13) mean (SD) Mean change from  6.4 (5.04)  2.2 (5.80) 4.20,<0.0001^(a), baseline (SD) [2.30, 6.10] <0.0001^(b) CI = confidenceinterval; ITT = intent-to-treat; LPFT = Leicester Peripheral Field Test;SD = standard deviation ^(a)P-value = 2-sided t-test ^(b)P-value =Wilcoxon test

TABLE 7 Mean Change from Baseline in Marginal Reflex Distance 1 in theStudy Eye (ITT Population), Study 1 Mean Difference, P-Value [95% CI]Test Vehicle P-Value^(b) Parameter N = 94 N = 46 Test vs Vehicle MeanMRD-1 at 1.16 (0.661) 1.03 (0.678) baseline, mm (SD) Mean change frombaseline in MRD-1 at primary efficacy time points, mm (SD) Day 1, Hour 6n = 94 n = 46 0.27, 0.1198^(a), 0.94 (0.924) 0.67 (1.001) [−0.07, 0.61]0.0276^(b) Day 14, Hour 2 n = 91 n = 46 0.52, 0.0007^(a), 1.09 (0.799)0.58 (0.875) [0.22, 0.81] 0.0004^(b) Mean change from baseline in MRD-1at remaining post-dosing time points, mm (SD) Day 1, Hour 2 n = 94 n =46 0.49, 0.0007^(a), 0.99 (0.776) 0.50 (0.803) [0.21, 0.77] <0.0001^(b)Day 1, Hour 8 n = 94 n = 46 0.24, 0.1491^(a), 0.93 (0.958) 0.70 (0.771)[−0.09, 0.56] 0.1701^(b) Day 14, Hour 6 n = 92 n = 45 0.33, 0.0477^(a),1.03 (0.856) 0.70 (0.985) [0.00, 0.65] 0.0101^(b) Day 14, Hour 8 n = 91n = 45 0.20, 0.2295^(a) 0.88 (0.857) 0.68 (1.023) [−0.13, 0.53]0.1511^(b) Day 42 n = 91 n = 45 0.46, 0.0160^(a), 1.25 (1.036) 0.79(1.020) [0.09, 0.83] 0.0113^(b) CI = confidence interval; ITT =intent-to-treat; MRD-1 = marginal reflex distance-1; SD = standarddeviation ^(a)P-value = 2-sided t-test ^(b)P-value = Wilcoxon test

Example 4 Phase 3 Data, Study 2

Study 2:

This Study was a multicenter, randomized, double-masked,placebo-controlled, Phase 3 study of the safety and efficacy of once perday dosing (QD) treatment (one drop per eye) with oxymetazolinehydrochloride compared to Vehicle in subjects with acquired ptosis. Atotal of 164 subjects were randomized in an approximate 2:1 ratio:oxymetazoline hydrochloride 0.1 wt % QD (N=109); Vehicle (N=55) at 27sites. Oxymetazoline hydrochloride 0.1 wt % was administered topicallyfor 42 days (6 weeks). The study was conducted in 2 periods; Period 1(safety and efficacy) was 2 weeks in duration, and Period 2 (extendedsafety and comfort) was 4 weeks in duration. The mean age of thesubjects was 63.5 years. One subject was younger than 18 years old.

4.1 Efficacy

Efficacy was assessed with the LPFT (primary) and photographicmeasurement of MRD-1. The primary efficacy endpoints were ordered in ahierarchy to compare oxymetazoline hydrochloride against vehicle on themean increase from baseline (Day 1 Hour 0) in the number of points seenon the top 4 rows of the LPFT in the study eye at:

-   -   1. Hour 6 on Day 1    -   2. Hour 2 on Day 14        The results are presented below. The increases at both time        points in the number of points seen in the superior visual field        (change in LPFT) in the oxymetazoline hydrochloride group        compared to the Vehicle group were statistically significant,        showing that the improvement in the superior visual field was        evident at 6 hours post-dose on Day 1 and 2 hours post-dose on        Day 14, Table 8.

Photographic measurement of MRD-1 also showed a positive effect withoxymetazoline hydrochloride treatment. Increases in LPFT werenumerically greater in the oxymetazoline hydrochloride group than in theVehicle group at all post-dosing time points. Greater MRD-1 increaseswere observed for the oxymetazoline hydrochloride group than the Vehiclegroup at all post-dosing time points for 6 weeks, Table 9. IncreasedMRD-1 values observed at 5 minutes post-dose indicated onset of actionby 5 minutes.

4.2 Safety

Oxymetazoline hydrochloride was well tolerated, and the AEs that wereobserved were predominantly mild in intensity.

4.3 Results

The LPFT was performed using a Humphrey Visual Field Analyzer. It is anage-corrected screening test with a three-zone strategy. Thirty-fivepoints are tested in the superior field while 14 points are tested inthe inferior field. A maximum of 48° is tested in the superior visualfield. The center of fixation is shifted 15° inferiorly to allow formaximum superior field testing (Ho et al., 2011). The inferior fieldtest serves as a reference but is not used in the analysis. Arepresentative Leicester Peripheral Field Test grid can be seen in FIG.2. Subjects keep their chin and forehead against the chin and foreheadrests, and keep their brows relaxed. Subjects look at the fixationtarget throughout the test. A corrective lens is not necessary on theLPFT unless the subject would have a difficult time seeing the targetwithout it (e.g., high myope, high hyperope, or high astigmat).

TABLE 8 Observed and Change from Baseline in Mean Points Seen inSuperior Visual Field on LPFT in the Study Eye at Primary Efficacy TimePoints (ITT Population), Study 2 Mean Difference, Points Seen inSuperior (95% CL), p-value^(a) Visual Field p-value^(b) OxymetazolineOxymetazoline Hydrochloride Vehicle Hydrochloride Parameter N = 109 N =55 vs Vehicle Mean points at 17.6 (4.92) 17.6 (5.48) baseline (SD) Meanpoints at primary efficacy time points Day 1, Hour 6, 23.9 (6.67) 19.7(6.16) observed mean (SD) Mean change from  6.3 (6.72)  2.1 (4.28) 4.23(2.36, 6.09), baseline (SD) <0.0001^(a) <0.0003^(b) Day 14, Hour 2, 25.3(6.35) 20.0 (5.84) observed mean (SD) Mean change from  7.7 (6.41)  2.4(5.26) 5.30 (3.45, 7.14), baseline (SD) <0.0001^(a) <0.0003^(b) CL =confidence limit; ITT = intent-to-treat; SD = standard deviation^(a)p-value (2-sided t-test) derived from ANCOVA model with treatment asa fixed factor and baseline score as a covariate ^(b)p-value (Wilcoxonrank sum test)Additional data from the above LPFT is detailed below in Table 9:

TABLE 9 Mean Change from Baseline in Marginal Reflex Distance 1 in theStudy Eye (ITT Population), Study 2 Mean Difference, (95% CL),p-value^(a) Oxymetazoline p-value^(b) Hydrochloride VehicleOxymetazoline Hydrochloride vs Parameter N = 109 N = 55 Vehicle MeanMRD-1 at baseline, mm 1.04 (0.735) 1.07 (0.697) — (SD) Mean change frombaseline in MRD-1 at primary efficacy time points, mm (SD) Day 1, 5minutes 0.59 (0.721) 0.20 (0.571) 0.38, (0.16, 0.59), 0.0007^(a)0.0007^(b) Day 1, 15 minutes 0.93 (0.811) 0.32 (0.641) 0.60, (0.36,0.84), <0.0001^(a) <0.0001^(b) Day 1, 2 hours 1.05 (0.903) 0.33 (0.555)0.71, (0.45, 0.96), <0.0001^(a) <0.0001^(b) Day 1, 6 hours 0.98 (0.867)0.35 (0.567) 0.61, (0.37, 0.86), <0.0001^(a) <0.0001^(b) Day 14, 0 hours0.37 (0.805) 0.40 (0.743) −0.04, (−0.29, 0.22), 0.7800^(a) 0.9648^(b)Day 14, 5 minutes 0.77 (0.853) 0.42 (0.775) 0.33, (0.07, 0.60),0.0151^(a) 0.0115^(b) Day 14, 15 minutes 1.11 (0.0.922) 0.41 (0.833)0.68, (0.39, 0.97), <0.0001^(a) <0.0001^(b) Day 14, 2 hours 1.22 (0.926)0.43 (0.734) 0.78, (0.50, 1.06), <0.0001^(a) <0.0001^(b) Day 14, 6 hours1.06 (0.902) 0.47 (0.737) 0.58, (0.31, 0.85), <0.0001^(a) <0.0001^(b)Day 42, 5 minutes 0.86 (0.849) 0.42 (0.799) 0.42, (0.15, 0.68),0.0020^(a) 0.0033^(b) Day 42, 15 minutes 1.04 (0.912) 0.47 (0.926) 0.55,(0.26, 0.84), 0.0003^(a) 0.0005^(b) CL = confidence limit; ITT =intent-to-treat; MRD-1 = marginal reflex distance 1; SD = standarddeviation ^(a)p-value (2-sided t-test) derived from ANCOVA model withtreatment as a fixed factor and baseline score as a covariate^(b)p-value (Wilcoxon rank sum test)

Example 5 Oxymetazoline HCl Formulation Stability

Stability testing was performed on oxymetazoline hydrochloridepreparations across a 24-month span at 40% relative humidity. Theresults of the stability testing are shown below in Table 10, andvehicle stability data can be found in Table 11.

TABLE 10 Stability Results Every 6 Months at 25° C./40% RH Time points(Months) Test Method Proposed Specification 0 6 12 18 24 Appearance EPSClear, colorless solution Conforms Conforms Conforms Conforms ConformsTP-042 free of any particulates or crystallization pH EPS SOP  5.8-6.86.5 6.4 6.5 6.5 6.4 SAS-013 Osmolality EPS SOP  290-330 mOsm/kg 315 304320 300 318 SAS-005 Viscosity EPS SOP   5-25 cps 24.9 NT NT NT NTSAS-057 Assay EPS 90.0-110.0% of Label 99.1% 96.5% 95.9% 95.2% 93.9%TP-101 Claim (1.0 mg/mL) ID by EPS HPLC TP-101 Conforms Conforms NT NTNT NT (USP) Related EPS TP-113 TBD (0.05% reporting Substances Limit)Unspecified Individual NT NT ND 0.13% ND RRT = 0.42 UnspecifiedIndividual NT NT 0.46% 0.73% 0.13% RRT = 0.50 Unspecified Individual NTNT 0.53% 0.79% 0.87% RRT = 0.54 -0.57 Unspecified Individual NT NT ND ND0.90 RRT = 0.61-62 Unspecified Individual NT NT 0.60% 0.79% ND RRT =0.81-0.86 Unspecified Individual NT NT 0.07% ND 1.01% RRT = 1.2Unspecified Individual NT NT 0.09% 0.10% 0.10% RRT = 1.9 Total RelatedNT NT 1.68% 2.61% 3.07% Substances (Report Results) Particulate EPSTP-034 ≥10 μm NMT 50 1 NT NT NT NT Matter microscopic per ml ≥25 μm NMT50 0 NT NT NT NT per ml ≥50 μm NMT 50 0 NT NT NT NT per ml NT = nottested

TABLE 11 Stability Results Every 6 Months at 25° C./40% RH (Vehicle)Time points (months) Test Method Proposed Specification 0 6 12 18 24Appearance EPS TP-042 Clear, colorless solution Conforms ConformsConforms Conforms Conforms free of any particulates or crystallizationpH EPS SOP  5.8-6.8 6.5 6.2 6.4 6.4 6.5 SAS-013 Osmolality EPS SOP 290-330 mOsm/kg 312 306 313 296 311 SAS-005 Viscosity EPS SOP   5-25cps 18.4 NT NT NT NT SAS-057 Assay EPS TP-101 90.0-110.0% of Label 0.0%NT NT NT NT Claim (1.0 mg/mL) ID by HPLC EPS TP-101 Conforms Conforms NTNT NT NT (USP) (none detected) Particulate EPS TP-034 ≥10 μm NMT 50 perml 1 NT NT NT NT Matter Microscopic ≥25 μm NMT 5 per ml 0 NT NT NT NT≥50 μm NMT 2 per ml 0 NT NT NT NT NT = not tested

Oxymetazoline hydrochloride solutions were stable across five timepoints measured at 0 months, 6 months, 12 months, 18 months, and 24months, showing good stability and shelf-life for the formulatedpreparations.

Example 6 Oxymetazoline HCl Clinical Supply Stability Study

Oxymetazoline hydrochloride formulations were prepared according toTable 12. Stability testing was performed on oxymetazoline preparationsacross a 24- and 30-month span.

TABLE 12 Summary of Batches Used in Clinical Studies, OxymetazolineHydrochloride Ophthalmic Solution, 0.1% (RVL-1201) Active Batch orContainer/ number Vehicle Batch size Closure/Fill 1680614 Active  3 L 1cc dropperette, 0.7 mL fill 1680615 Vehicle  3 L 1 cc dropperette, 0.7mL fill RD427 Active 150 kg 0.5 mL BFS in foil pouch, 0.34 mL fillR1D425 Vehicle 150 kg 0.5 mL BFS in foil pouch, 0.34 mL fill R80261Active 200 kg 0.5 mL BFS in foil pouch, 0.34 mL fill R80251 Vehicle 200kg 0.5 mL BFS in foil pouch, 0.34 mL fill

Three commercial-scale, one-stage process batches (R60681, R60701, andR60711) were tested at the end of shelf-life, and the results supportthe proposed 24-month shelf-life. The 24 month and 30-month stabilitydata are presented in FIGS. 3A-3B, 4A-4B, and 5A-5B for each batch(R60681, R60701, and R60711, respectively).

Throughout this application, various publications are referenced inparentheses by author name and date, or by Patent No. or PatentPublication No. The disclosures of these publications are herebyincorporated in their entireties by reference into this application inorder to more fully describe the state of the art as known to thoseskilled therein as of the date of the disclosure described and claimedherein. However, the citation of a reference herein should not beconstrued as an acknowledgement that such reference is prior art to thepresent disclosure.

What is claimed is:
 1. A single use container comprising an aqueouspharmaceutically stable ophthalmic formulation comprising: a) about 0.1wt % oxymetazoline hydrochloride; b) about 0.64 wt % sodium chloride; c)about 0.075 wt % potassium chloride; d) about 0.048 wt % calciumchloride dihydrate; e) about 0.03 wt % magnesium chloride hexahydrate;f) about 0.39 wt % sodium acetate trihydrate and about 0.17 wt % sodiumcitrate; and g) about 0.5 wt % hypromellose; wherein the formulation hasa pH range from about 5.8 to about 6.8, wherein the formulation has aviscosity of from about 15 cPs to about 35 cPs, wherein the formulationis stable at 25° C. and 40% relative humidity for a period of at least24 months, and wherein the formulation does not comprise a preservative.2. The formulation of claim 1, wherein the formulation further comprisesa pH adjuster selected from the group consisting of acetic acid,hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calciumacetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate,sodium hydroxide, ammonium hydroxide, ammonium phosphate, and acombination thereof.
 3. The formulation of claim 2, wherein the pHadjuster comprises hydrochloric acid.
 4. The single use container ofclaim 1, wherein the volume of the single use container is about 0.5 mL.5. The single use container of claim 4, wherein the single use containeris in a child resistant pouch.
 6. The single use container of claim 1,wherein the single use container delivers about 0.035 mg ofoxymetazoline hydrochloride per drop.
 7. An aqueous pharmaceuticallystable ophthalmic formulation consisting of: a. about 0.1 wt %oxymetazoline hydrochloride; b. about 0.64 wt % sodium chloride; c.about 0.075 wt % potassium chloride; d. about 0.048 wt % calciumchloride dihydrate; e. about 0.03 wt % magnesium chloride hexahydrate;f. about 0.39 wt % sodium acetate trihydrate and about 0.17 wt % sodiumcitrate; g. about 0.5 wt % hypromellose; h. a pH adjuster; and i. waterQS; wherein the formulation has a pH range from about 5.8 to about 6.8,wherein the formulation has a viscosity of from about 15 cPs to about 35cPs and wherein the formulation is stable at 25° C. and 40% relativehumidity for a period of at least 24 months.
 8. A single use containercomprising the formulation of claim
 7. 9. The single use container ofclaim 8, wherein the volume of the single use container is about 0.5 mL.10. The single use container of claim 8, wherein the single usecontainer is in child resistant packaging.
 11. The single use containerof claim 8, wherein the single use container delivers about 0.035 mg ofoxymetazoline hydrochloride per drop.
 12. A single use containercomprising an aqueous pharmaceutically stable ophthalmicpreservative-free formulation comprising: a. 0.1 wt % oxymetazolinehydrochloride; b. 0.64 wt % sodium chloride; c. 0.075 wt % potassiumchloride; d. 0.048 wt % calcium chloride dihydrate; e. 0.03 wt %magnesium chloride hexahydrate; f. 0.39 wt % sodium acetate trihydrateand 0.17 wt % sodium citrate; and g. 0.5 wt % hypromellose; wherein theformulation has a pH range from about 5.8 to about 6.8, wherein theformulation has a viscosity of from about 15 cPs to about 35 cPs andwherein the formulation is stable at 25° C. and 40% relative humidityfor a period of at least 24 months.
 13. The single use container ofclaim 1, wherein the formulation has a pH range from about 6.3 to about6.5.
 14. The formulation of claim 7, wherein the formulation has a pHrange from about 6.3 to about 6.5.
 15. The single use container of claim12, wherein the formulation has a pH range from about 6.3 to about 6.5.16. The single use container of claim 1, wherein the sodium citrate issodium citrate dihydrate.
 17. The formulation of claim 7, wherein thesodium citrate is sodium citrate dihydrate.
 18. The single use containerof claim 12, wherein the sodium citrate is sodium citrate dihydrate. 19.The formulation of claim 7, wherein the pH adjuster is hydrochloricacid.